Targeting HER2 expression in cancer: New drugs and new indications.

Functional activation of human epidermal growth factor receptor 2 (HER2) has been shown to strongly promote carcinogenesis, leading to the investigation of HER2-directed agents in cancers with HER2 genomic alterations. This has been best documented in the context of HER2 gene amplification in breast and gastric/gastroesophageal junction carcinomas for which several HER2-directed agents are available and have become a part of standard treatment regimens. Somatic HER2 gene mutations have been recently described at low frequency in a variety of human cancers and have emerged as a novel predictive biomarker for HER2-directed therapies. Preclinical data also indicate that activating HER2 mutations are potent oncogenic drivers in a manner that is analogous to HER2 amplification. HER2 mutations may clinically confer sensitivity to HER2-directed agents as recently shown in a phase II clinical trial with antibody-drug conjugate against HER2 trastuzumab deruxtecan in patients with non-squamous non-small cell lung carcinoma

Sacituzumab govitecan expands its therapeutic spectrum among breast cancer subtypes

Antibody-drug conjugates (ADCs) are novel, highly potent drugs composed of a small molecule of an anticancer drug (payload) attached to humanized antibody recognizing an epitope on the surface of cancer cells. ADCs are rapidly expanding in the oncology field. By 2022, >180 ADC-based clinical trials have been conducted [1]. Most of these clinical trials are in phases I or II [1]. Several ADCs have been approved and used for the treatment of various malignancies (e.g., brentuximab vedotin (BV) for the treatment of CD30+ lymphomas, trastuzumab emtansine (T-DM1) for advanced/metastatic/or early-stage high-risk HER2-positive breast cancer with residual disease after neoadjuvant treatment) [2]. Read more in the PDF

Comment on the manuscript “Histological subtype is associated with PD-L1 expression and CD8+ T-cell infiltrates in triple-negative breast carcinoma” by Salisbury et al. (Ann Diagn Pathol 2022; 57: 151901, https://doi.org/10.1016/j.anndiagpath.2022.151901)

I read with great interest a recent paper written by Salisbury et al. published in the April 2022 issue of the Annals of Diagnostic Pathology [1]. In their study, the authors explored a small cohort of triple-negative breast carcinomas (TNBC) for biomarkers of response to immune checkpoint inhibitors. They also analyzed the tumor-infiltrating lymphocytes, the percentage and ratio between the CD4+ and CD8+ T-cells. The topic is highly relevant given the recent “booming” and advances in the field followed by the Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors for the treatment of TNBC: Atezolizumab, which was initially approved and then withdrawn voluntarily by Genentech in August 2021, and pembrolizumab, which was approved in July 2021. For the PD-L1 assessment, the authors employed two corresponding and approved companion diagnostic (CDx) tests, namely SP142 (Ventana) and 22C3 (Agilent) antibodies, revealing some essential discrepancies that had been previously reported. Notably, they also used two different scoring systems for the two antibodies of which combined positive score (CPS) also takes into account the PD-L1 expression in the tumors cells (CPS = “Number of PD-L1–positive cells/Tumor cells, lymphocytes, and macrophages/divided by the total number of viable tumor cells in the assessed area, multiplied by 100”). However, they did not report the PD-L1 expression in the tumor cells, which would be helpful to know. In addition, some images highlighting the observed discrepancies would be very welcome for pathology journals like Annals of Diagnostic Pathology. In my experience, some cancers like metaplastic (spindle cell variant) carcinoma frequently exhibit PD-L1 expression on the tumor cells [2]. Although they had a small metaplastic carcinoma cohort (n = 5), they did not provide the morphologic subtypes of metaplastic carcinomas. On the other hand, apocrine carcinomas tend to be PD-L1 negative, as confirmed in this study. In addition, apocrine carcinomas exhibit a low tumor mutational burden (TMB) and are microsatellite stable (MSS), as reported in several recent studies [3], [4], [5]. The molecular features make apocrine carcinoma patients less likely to benefit from immune checkpoint inhibitors

The Role of Pathology in the Era of Personalized (Precision) Medicine: A Brief Review.

This review provides a brief overview of the state-of-the-art molecular pathology approaches emphasizing the increasingly important pathology role in clinical precision cancer medicine. Recent advances in molecular biology and genetics have tremendously affected the practice of anatomic pathology, gradually transforming it from a morphology-based into a molecularbased discipline. Molecular diagnostics has a long tradition in pathology, especially in clinical pathology. The improvement of methodology for genomic testing in recent years has made it one of the cornerstones of precision cancer medicine. The decisions related to cancer treatments are no longer solely based on the histopathological diagnosis. Various genomic analyses of human cancers are being incorporated into diagnostic and decision-making algorithms. CONCLUSION: The pathologists continue to play an essential role in developing and implementing molecular and genomic tests in practice and communicate the results and their relevance with clinicians. Such activities are of utmost importance for successfully translating scientific advancements into a benefit to patients ("next-generation pathologists")

PD-L1 testing by immunohistochemistry in Immuno-Oncology.

Immunotherapy, based on immune checkpoint inhibitors targeting the Programmed cell death ligand 1 (PD-L1) and/or Programmed Death Receptor 1 (PD-1), has substantially improved the outcomes of patients with various cancers. However, only ~30% of patients benefit from immune checkpoint inhibitors. Tumor PD-L1 expression, assessed by immunohistochemistry, is the most widely validated and used predictive biomarker to guide the selection of patients for immune checkpoint inhibitors. PD-L1 assessment may be challenging due to the necessity for different companion diagnostic assays for required specific immune checkpoint inhibitors and a relatively high level of inter-assay variability in terms of performance and cutoff levels. In this review, we discuss the role of PD-L1 immunohistochemistry as a predictive test in immunotherapy (immuno-oncology), highlight the complexity of the PD-L1 testing landscape, discuss various preanalytical, analytical and clinical issues that are associated with PD-L1 assays, and provide some insights into optimization of PD-L1 as a predictive biomarker in immuno-oncology

PD-L1 testing by immunohistochemistry in immuno-oncology

Immunotherapy, based on immune checkpoint inhibitors targeting the Programmed cell death ligand 1 (PD-L1) and/or Programmed Death Receptor 1 (PD-1), has substantially improved the outcomes of patients with various cancers. However, only ~30% of patients benefit from immune checkpoint inhibitors. Tumor PD-L1 expression, assessed by immunohistochemistry, is the most widely validated and used predictive biomarker to guide the selection of patients for immune checkpoint inhibitors. PD-L1 assessment may be challenging due to the necessity for different companion diagnostic assays for required specific immune checkpoint inhibitors and a relatively high level of inter-assay variability in terms of performance and cutoff levels. In this review, we discuss the role of PD-L1 immunohistochemistry as a predictive test in immunotherapy (immuno-oncology), highlight the complexity of the PD-L1 testing landscape, discuss various preanalytical, analytical and clinical issues that are associated with PD-L1 assays, and provide some insights into optimization of PD-L1 as a predictive biomarker in immuno-oncology

Decreased number of acute appendicitis cases in pediatric population during the COVID-19 pandemic: Any link?

The reasons behind the decrease in AA frequency during the COVID-19 pandemic remain unclear. Some authors have proposed that milder forms can be treated conservatively at home [15] or using antibiotics. Snapiri et al. also reported delays in diagnosing AA in seven pediatric patients having complicated forms of AA. We believe that other factors may contribute to the decrease including various infectious agents (viruses, bacteria, fungi and parasites) whose exposure in the pediatric population and a potential link to AA have been proposed. It is also well-known that some of these pathogens may give specific histomorphological forms of AA. During the lockdown period, it is likely that the exposure to various microbes has been substantially reduced and consequently affected the frequency of AA in pediatric population. Regardless the causes and numbers, all pediatric emergencies, including AA, during the COVID-19 pandemic should be promptly treated as any delay in their diagnosis and treatment may be as big of a threat as the COVID-19 virus itself

Novel regulators of PD-L1 expression in cancer: CMTM6 and CMTM4-a new avenue to enhance the therapeutic benefits of immune checkpoint inhibitors.

CMTM6 and CMTM4-a new avenue to enhance the therapeutic benefits of immune checkpoint inhibitor

An Update on the Molecular and Clinical Characteristics of Apocrine Carcinoma of the Breast

Apocrine carcinoma of the breast is a rare malignancy. According to 2019 WHO classification, apocrine cellular features and a characteristic steroid receptor profile (Estrogen receptor (ER)-negative and androgen receptor (AR)-positive) define apocrine carcinoma. Her-2/neu protein expression is reported in ∼30-50% of apocrine carcinomas, while NGS analysis showed frequent PIK3CA/PTEN/AKT and TP53 mutations Followed by deregulation in the mitogen-activated protein kinase (MAPK) pathway components (mutations of KRAS, NRAS, BRAF). A recent miRNA study indicates various miRNAs (downregulated hsa-miR-145-5p and upregulated 14 miRNAs such as hsa-miR-182-5p, hsa-miR-3135b, and hsa-miR-4417) may target the commonly altered pathways in apocrine carcinomas such as ERBB2/HER2 and MAPK signaling pathway. Although AR expression is a hallmark of apocrine carcinoma, little is known regarding the efficacy/resistance to antiandrogens. Success of bicalutamide, a non-steroidal anti-androgen, was reported in a case of Her2-negative apocrine carcinoma. Two recent studies, however, described presence of anti-androgen resistance biomarkers (a splice variant ARv7 and AR/NCOA2 co-amplification) in a subset of AR+ apocrine carcinomas, cautioning the use of anti-androgens in AR+ triple-negative breast carcinomas. Apocrine carcinomas rarely show biomarkers predictive of response to immune checkpoint inhibitors (PD-L1 expression, MSI-H status, and TMB-high). Therefore, a comprehensive cancer profiling of apocrine carcinomas is necessary to identify potential therapeutic targets for a truly individualized treatment approach

Trop-2 protein as a therapeutic target: A focused review on Trop-2-based antibody-drug conjugates and their predictive biomarkers

Antibody-drug conjugates represent a new class of highly potent antineoplastic drugs built by attaching a small molecule of an anticancer drug (payload) or another therapeutic agent to an antibody recognizing an epitope on the targeted cells. Trophoblast cell-surface antigen-2 (Trop-2) was originally described in trophoblasts and fetal tissues, but subsequently its overexpression has been demonstrated in various solid malignan-cies. Sacituzumab govitecan (SG), a conjugate of anti-Trop-2 antibody and SN-38 payload (an active metabolite of irinotecan), is the first in the class that has been clinically validated and approved by the Food and Drug Administration for the treatment of metastatic triple-negative breast (2020) and urothelial carcinomas (2021). In the current review, we summarize and critically appraise the most recent advances with regard to SG, emphasizing the predictive biomarker analysis.Scopu