Immunohistochemistry of the PD-L1 protein may be predictive for anti-PD-1 and anti-PD-L1 immunotherapy in pulmonary adenocarcinoma and in clinically unselected cohorts of so-called non-small-cell ...lung cancer. Several PD-L1 immunohistochemistry assays with custom reagents and scoring-criteria are developed in parallel. Biomarker testing and clinical decision making would profit from harmonized PD-L1 diagnostics. To assess interobserver concordance and PD-L1 immunohistochemistry staining patterns, 15 pulmonary carcinoma resection specimens (adenocarcinoma: n=11, squamous-cell carcinoma: n=4) were centrally stained with the assays 28-8, 22C3, SP142, and SP263 according to clinical trial protocols. The slides were evaluated independently by nine pathologists. Proportions of PD-L1-positive carcinoma cells and immune cells were scored according to a 6-step system that integrates the criteria employed by the four PD-L1 immunohistochemistry assays. Proportion scoring of PD-L1-positive carcinoma cells showed moderate interobserver concordance coefficients for the 6-step scoring system (Light's kappa=0.47–0.50). The integrated dichotomous proportion cut-offs (≥1, ≥5, ≥10, ≥50%) showed good concordance coefficients (κ=0.6–0.8). Proportion scoring of PD-L1-positive immune cells yielded low interobserver concordance coefficients both for the 6-step-score (κ<0.2) and the dichotomous cut-offs (κ=0.12–0.25). The assays 28-8 and 22C3 stained similar proportions of carcinoma cells in 12 of 15 cases. SP142 stained fewer carcinoma cells compared to 28-8, 22C3, and SP263 in four cases, whereas SP263 stained more carcinoma cells in nine cases. SP142 and SP263 stained immune cells more intensely. The data indicate that carcinoma cells can be reproducibly scored in PD-L1 immunohistochemistry for pulmonary adenocarcinoma and squamous-cell carcinoma. No differences in interobserver concordance were noticed among the tested assays. The scoring of immune cells yielded low concordance rates and might require specific standardization. The four tested PD-L1 assays did not show comparable staining patterns in all cases. Thus, studies that correlate staining patterns and response to immunotherapy are required to test the significance of the observed differences.
Aims
Programmed death ligand 1 (PD‐L1) immunohistochemistry has become a mandatory diagnostic test in the treatment of lung cancer. Several research initiatives have started to harmonise the five ...PD‐L1 immunohistochemistry assays that have been used in clinical trials. Here, we report data on interlaboratory and interassay concordance for commercial assays (‘assays’) and laboratory‐developed tests (LDTs) at 10 German testing sites.
Methods and results
To assess interlaboratory concordance, a tissue microarray containing 21 pulmonary carcinoma specimens was centrally prepared. Pre‐cut sections were stained at 10 sites by the use of assays 28‐8, 22C3, SP263, and SP142, as well as 11 LDTs. Assay performance was evaluated with a second tissue microarray containing 11 cell lines with defined PD‐L1 expression. Quality control was centrally performed by manual and digital analyses. The assays yielded reproducible IHC staining patterns at all sites. In agreement with previous studies, 22C3, 28‐8 and SP263 showed similar staining patterns, whereas SP142 was distinct. Among the LDTs, six of 11 protocols showed staining patterns similar to those of assays 22C3 and 28‐8. Interlaboratory concordance of tumour cell scoring by use of a six‐step system was moderate (Light's κ = 0.43–0.69), whereas the clinically approved cut‐offs of ≥1% and ≥50% showed substantial concordance (κ = 0.73–0.89). Immune cell scoring by the use of SP142 yielded moderate concordance (κ = 0.42).
Conclusions
The data confirm the previously described staining patterns of the assays, and show that they can be reproducibly employed at different sites. LDTs with staining results similar to those of the assays are implementable, but have to be carefully validated.
Mutations and activation of the PI3K signaling pathway in breast cancer cells have been linked to brain metastases. However, here we describe that in some breast cancer brain metastases samples the ...protein expression of PI3K signaling components is restricted to the metastatic microenvironment. In contrast to the therapeutic effects of PI3K inhibition on the breast cancer cells, the reaction of the brain microenvironment is less understood. Therefore we aimed to quantify the PI3K pathway activity in breast cancer brain metastasis and investigate the effects of PI3K inhibition on the central nervous system (CNS) microenvironment. First, to systematically quantify the PI3K pathway activity in breast cancer brain metastases, we performed a prospective biomarker study using a reverse phase protein array (RPPA). The majority, namely 30 out of 48 (62.5%) brain metastatic tissues examined, revealed high PI3K signaling activity that was associated with a median overall survival (OS) of 9.41 months, while that of patients, whose brain metastases showed only moderate or low PI3K activity, amounted to only 1.93 and 6.71 months, respectively. Second, we identified PI3K as a master regulator of metastasis‐promoting macrophages/microglia during CNS colonization; and treatment with buparlisib (BKM120), a pan‐PI3K Class I inhibitor with a good blood‐brain‐barrier penetrance, reduced their metastasis‐promoting features. In conclusion, PI3K signaling is active in the majority of breast cancer brain metastases. Since PI3K inhibition does not only affect the metastatic cells but also re‐educates the metastasis‐promoting macrophages/microglia, PI3K inhibition may hold considerable promise in the treatment of brain metastasis and the respective microenvironment.
Main Points
Blockade of PI3K signaling in macrophages/microglia in brain metastasis models leads to (a) a more metastasis‐suppressing macrophage phenotype, (b) changes in the astrogliosis, and (c) reduced tumor cell infiltration into the brain parenchyma.
Background and Objectives
Primary pulmonary sarcoma (PPS) accounts for less than 1.1% of all pulmonary tumors. Few outcome data are reported. We evaluated outcome and prognostic factors in our ...series.
Methods
We retrospectively reviewed all patients who underwent resection for PPS in our center from 2002 to 2018. Survival was calculated from the date of surgery until last follow‐up. Impact on survival of gender, type of lung resection, completeness of resection, grade, size, and TNM staging for lung cancer and soft tissue sarcoma (STS) was assessed.
Results
Thirteen patients were included. Eight (61.5%) patients received neoadjuvant treatment. Median tumor size at diagnosis was 11.5 cm (1‐30 cm). Type of lung resection was wedge (n = 2, 15%), lobectomy (n = 4, 31%), intrapericardial (n = 3, 23%), and extrapleural pneumonectomies (n = 4, 31%). In‐hospital mortality was 8%. Overall 5‐year survival was 60%. Median disease‐free survival was 17 months. Tumor size was a predictor for survival (P = .02) and recurrence (P = .05). Gender (P = .04) and type of lung resection (P = .04) were predictors of survival. T stage for STS of trunk and extremity, and TNM stage for lung cancer were predictors for recurrence (P = .03 and P = .04, respectively).
Conclusion
Surgical resection within a multimodality therapy concept in highly selected patients can offer good long‐term outcome.
The relatively recent discovery of neurotrophic tropomyosin receptor kinase (NTRK) gene arrangements as pan-tumor predictive biomarkers has led to impressive novel treatments for patients with TRK ...fusions. Although the number of patients who qualify for treatment is vanishingly small for cancer patients in general, a few histological subsets of sarcomas exhibit NTRK fusions more commonly leading to large expectations within the sarcoma community.
Larotrectenib and entrectenib have recently been approved based on durable responses in TRK positive cancers with nonresectable or metastatic disease, including many sarcomas. Identification of resistance mutations to TRKi has led to the development of novel salvage therapies which may soon further expand the armamentarium of treatments. The greatest barrier and frustration to date is the actual identification of patients who harbor the fusion. The dimension of rarity in sarcomas remains difficult to comprehend for both patients and caregivers. Diagnosis of NTRK fusions is complex, particularly in the context of sarcomas and can involve immunohistochemistry as a screening tool but frequently requires fluorescence-in-situ hybridization or next-generation sequencing (NGS) to confirm the diagnosis.
The growing evidence on subtype-specific incidence of NTRK fusions will help to improve strategic prioritization or exclusion of subtypes to reduce the burden of negative testing. Next-generation inhibitors provide potential salvage treatment options for patients failing first-line therapy.
MET is a potential therapeutic target in lung cancer and both MET tyrosine kinase inhibitors and monoclonal antibodies have entered clinical trials. MET signaling can be activated by various ...mechanisms, including gene amplification. In this study, we aimed to investigate MET amplification status in adeno- and squamous cell carcinomas of the lung. We propose clearly defined amplification scores and provide epidemiologic data on MET amplification in lung cancer.
We evaluated the prevalence of increased MET gene copy numbers in 693 treatment-naïve cancers by FISH, defined clear cutoff criteria, and correlated FISH results to MET IHC.
Two thirds (67%) of lung cancers do not have gains in MET gene copy numbers, whereas 3% show a clear-cut high-level amplification (MET/centromer7 ratio ≥2.0 or average gene copy number per nucleus ≥6.0 or ≥10% of tumor cells containing ≥15 MET copies). The remaining cases can be subdivided into intermediate- (6%) and low-level gains (24%). Importantly, MET amplifications occur at equal frequencies in squamous and adenocarcinomas without or with EGFR or KRAS mutations.
MET amplification is not a mutually exclusive genetic event in therapy-naïve non-small cell lung cancer. Our data suggest that it might be useful to determine MET amplification (i) before EGFR inhibitor treatment to identify possible primary resistance to anti-EGFR treatment, and (ii) to select cases that harbor KRAS mutations additionally to MET amplification and, thus, may not benefit from MET inhibition. Furthermore, our study provides comprehensive epidemiologic data for upcoming trials with various MET inhibitors.
Purpose: Patients affected by neurofibromatosis type 1 (NF-1) have an increased risk of developing gastrointestinal stromal tumors
(GIST). NF-1–associated GISTs are usually wild type for c-KIT and ...platelet-derived growth factor receptor-α (PDGFR-α) mutations
and harbor a different oncogenic molecular mechanism. The lack of data on imatinib activity raises the question whether to
enroll these patients in clinical trials. We analyzed a large series of NF-1 related GISTs to discuss the therapeutic implications.
Materials and Methods: Clinical, pathologic (IHC to CD34, S100, bcl-2, PDGFRA), and molecular features (exons 9, 11, 13, 14, 17 in c-kit and exons
12, 14, 18 in PDGFRA) of 28 patients were analyzed.
Results: The most common site of primary lesions was the small bowel (75%). Twelve patients (43%) had multiple tumors. Most tumors
belonged to the high (30.5%) or intermediate risk group for malignant behavior (39%). Three patients developed peritoneal
and liver metastases; another four had peritoneal spread only. All tumors were immunohistochemically strongly positive for
CD117. Three primary KIT/PDGFRA activating mutations were found. Three metastatic patients treated with imatinib experienced
progression, and only one had temporary stable disease. Median survival after starting treatment with imatinib was 21 months.
Conclusions: This study is the largest series available and confirms that KIT/PDGFRA mutations in NF-1–associated GISTs are sporadic.
Prognosis of metastatic tumors is poor, and imatinib response rate is low. Patients with NF-1–GIST of high or intermediate
risk should not be eligible for adjuvant trials of imatinib. Imatinib should not be used in a neoadjuvant intent in these
patients, and molecular analysis of activating mutations is strongly recommended.
PDF
