Potential novel therapy targets in neuroendocrine carcinomas of the breast

Neuroendocrine carcinoma (NEC) of the breast is a rare, special type of breast cancer, reportedly constituting 2% to 5% of all breast cancers. Although breast NEC does not have a specific targeted therapy, several new targeted therapies based on specific biomarkers were recently investigated in the NEC of lung and in other types of breast carcinoma, which may provide guidance to their feasibility in breast NEC. Twenty breast NECs were profiled for biomarkers of therapy including antibody-drug conjugates (DLL3, TROP-2, and FOLR1), histone deacetylase (H3K36Me3) inhibitors, tropomyosin receptor kinases (NTRK1/2/3 gene fusions) targeted inhibitors, alkylating agents (MGMT), and immune checkpoint inhibitors (PD-L1, TMB, and MSI) using immunohistochemistry and DNA/RNA next-generation sequencing assays. Predictive expression of TROP-2, FOLR1, and H3K36Me3 were detected in different subsets of tumors and may pave the way for development of novel targeted therapies in some patients with breast NECs. There was no evidence of DLL3 expression, NTRK gene fusions, or MGMT hypermethylation. No biomarkers predictive of immune checkpoint inhibitor efficacy (programmed death-ligand 1 expression, tumor mutational burden, microsatellite instability) were identified. FGFR and CCND1 gene amplifications were detected in isolated cases. This study identified several potential targets for novel therapies in breast NEC, including farletuzumab and mirvetuximab soravtansine (FOLR1), sacituzumab govitecan (TROP-2), and HDAC inhibitors (H3K36Me3). In some cases, CCND1 gene amplification may indicate the usefulness of investigational therapies. The reported results should serve as an early indication of potential clinical relevance in selected patients with breast NEC

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

Microsatellite instability status predicts response to anti-PD-1/PD-L1 therapy regardless the histotype: A comment on recent advances

It is well-known that somatic mutations resulting in increased number of neoantigens (“immunogenic antigens”) may enhance anti-tumor immune cell reaction. Also, high tumor mutation burden (load) [TML] is associated with improved response, durable clinical benefits and better outcome if a cancer is treated with immune check point inhibitors [anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-1/PD-L1) drugs] [1]. A subset of colorectal carcinomas (CRC) and other cancers characterized by mismatch repair deficiency (MMR) and/or microsatellite instability high (MSI-H) profiles may be particularly sensitive to the PD-1/PD-L1 blockade with immune check point inhibitors due to the common PD-L1/PD-L1 expression [2-9]. Several therapeutic antibodies inhibiting either PD-1 (nivolumab, pembrolizumab) or PD-L1 (MPDL3280A, Medi4736, BMS-936559) have been developed and approved for the treatment of various malignancies including malignant melanoma, non-small cell lung carcinoma, renal cell carcinoma, bladder carcinoma, Merkel cell carcinoma, and classical Hodgkin lymphoma [10]. A pivotal phase 2 study by Le et al. [11] highlighted the importance of mismatch-repair status in prediction of the clinical benefit of immune checkpoint blockade with pembrolizumab (anti-PD-1 drug) [11]. The study included 41 patients with progressive cancers of both CRC and non-colorectal origins and known MSI status. For CRC patients, the objective response rate and progression-free survival rate were 40% and 78%, respectively for mismatch repair-deficient tumors and 0% and 11% for mismatch repair-proficient CRCs. A novel study by Le et al. [12] (ClinicalTrials.gov number, NCT01876511) represents an extended analysis on the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers. The study included 86 patients with 12 different histologic cancer subtypes and proved mismatch repair-deficiency status assessed by either polymerase chain reaction (PCR) or immunohistochemistry. The data presented in this study indicate objective radiographic responses in 53% of patients while complete responses were achieved in 21% of patients. Based on this and previous data, on May 23, 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval to anti-PD-L1 drug pembrolizumab (KEYTRUDA®, Merck & Co.) for adult and pediatric patients with unresectable/metastatic MSI-H/MMR deficient solid tumors (regardless the histotype) that have progressed following prior treatment and without satisfactory alternative treatment modalities. The approval also covered MSI-H CRC patients who progressed following treatment with a classic cytotoxic therapy (fluoropyrimidine, oxaliplatin, and irinotecan). Taken together, these results revolutionize the cancer treatment paradigm as for the first time the cancer treatment was based solely on the molecular characteristics of cancer (in this case microsatellite instability/MSI/ status) regardless the tumor morphology (histotype). This appears to be “the FDA’s first tissue/site-agnostic approval”. Certainly, there are still ongoing but unresolved issues regarding these treatments including other merging predictive biomarkers (optimization of PD-L1 and PD-1 evaluation, e.g. tumor versus immune cell expression; cutoffs for positivity; selection of detection antibodies), tumor mutational load and the tumor neoantigen heterogeneity/specificity [13-15]. Further studies should also elucidate the mechanisms of recently described resistance to immune checkpoint inhibitors [16-18]

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

Disseminated histiocytoses biomarkers beyond BRAFV600E: frequent expression of PD-L1.

The histiocytoses are rare tumors characterized by the primary accumulation and tissue infiltration of histiocytes and dendritic cells. Identification of the activating BRAFV600E mutation in Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) cases provided the basis for the treatment with BRAF and/or MEK inhibitors, but additional treatment options are needed. Twenty-four cases of neoplastic histiocytic diseases [11 extrapulmonary LCH, 4 ECD, 4 extranodal Rosai-Dorfman disease (RDD), 3 follicular dendritic cell sarcoma (FDCS), 1 histiocytic sarcoma (HS) and 1 blastic plasmacytoid dendritic cell neoplasm (BPDCN)] were analyzed using immunohistochemical and mutational analysis in search of biomarkers for targeted therapy. BRAF V600E mutations were detected in 4/11 LCH and 4/4 ECD cases. A pathogenic PTEN gene mutation and loss of PTEN protein expression were identified in the case of HS. Increased expression of PD-L1 (≥2+/≥5%) was seen in 3/4 ECD, 7/8 LCH, 3/3 FDCS and 1/1 HS, with overall 81% concordance between 2 antibodies used in the study (SP142 vs. MAB1561 clone). These results show for the first time significant expression of the PD-L1 immune checkpoint protein in these disorders, which may provide rationale for addition of immune check-point inhibitors in treatment of disseminated and/or refractory histiocytoses