Classical pathology and mutational load of breast cancer – integration of two worlds

Budczies, Jan; Bockmayr, Michael; Denkert, Carsten; Klauschen, Frederick; Lennerz, Jochen K.; Győrffy, Balázs; Dietel, Manfred; Loibl, Sibylle; Weichert, Wilko; Stenzinger, Albrecht

doi:10.1002/cjp2.25

Cited by 98 publications

(77 citation statements)

References 56 publications

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“…TIL density is a crucial surrogate reflecting immune responsiveness to tumor peptide. TNBC is more densely infiltrated with lymphocytes than other subtypes 23, which may be partly explained by its high genetic instability and mutational load 24, 25. Aberrant proteins, termed neoantigens, encoded by mutated genes are more likely recognized by T cells as foreign than are non-mutant proteins and may provoke a more brisk lymphocytic reaction 26.…”

Section: Discussionmentioning

confidence: 99%

Strong Correlation of Indoleamine 2,3-Dioxygenase 1 Expression with Basal-Like Phenotype and Increased Lymphocytic Infiltration in Triple-Negative Breast Cancer

et al. 2017

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Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme involved in tumor immune escape. Blockade of the IDO1 pathway is an emerging modality of cancer immunotherapy. Triple-negative breast cancer (TNBC) lacks established therapeutic targets and may be a good candidate for this novel immunotherapeutic agent. The purpose of this study was to evaluate the clinicopathologic characteristics of the IDO1-expressing TNBC subset. A tissue microarray was constructed from 200 patients with TNBC. Immunohistochemistry (IHC) for IDO1 and TNBC molecular subtype-surrogate markers (AR, GCDFP-15, claudin-3, E-cadherin, CK5/6, and EGFR) was performed using this tissue microarray. Real-time polymerase chain reaction was performed to confirm the IDO1 mRNA expression level in 16 fresh-frozen TNBC samples. Two hundred TNBCs were classified into four subtypes based on surrogate IHC results: 22 luminal androgen receptor type (11.0%), 23 claudin-low type (11.4%), 103 basal-like type (51.5%), and 52 mixed type (26.0%). IDO1 positivity (defined as expression of >10% tumor cells) was observed in 37% of all TNBCs. IDO1 IHC expression was well correlated with mRNA expression. IDO1 positivity was significantly associated with smaller tumor size, dense stromal lymphocytic infiltration, and basal-like phenotype; however, it did not affect the patients' prognosis. IDO1 expression in basal-like TNBCs is considered an immune inhibitory signal that counterbalances active immunity and may reflect the high mutational load of these tumors. Our results suggest which patients with TNBC would be more efficaciously treated with IDO1 blockade.

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Section: Discussionmentioning

confidence: 99%

Strong Correlation of Indoleamine 2,3-Dioxygenase 1 Expression with Basal-Like Phenotype and Increased Lymphocytic Infiltration in Triple-Negative Breast Cancer

et al. 2017

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“…As matching tissue material harbored the very same genetic aberrations, these are high‐confidence results that may also support pathological tumor typing. With respect to diagnostic applications, detection of, for example, CDH1 mutations can aid conventional cytology and IHC in diagnosing lobular breast carcinoma . A patient in our cohort (c5), who was initially diagnosed with metastatic papillary thyroid cancer at a secondary care hospital, eventually developed ascites and peritoneal carcinomatosis.…”

Section: Discussionmentioning

confidence: 99%

Targeted deep sequencing of effusion cytology samples is feasible, informs spatiotemporal tumor evolution, and has clinical and diagnostic utility

Leichsenring

Volckmar

Kirchner

et al. 2017

Genes Chromosomes & Cancer

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During the course of disease, many cancer patients eventually present with metastatic disease including peritoneal or pleural spread. In this context, cytology specimens derived from ascites or pleural effusion may help to differentiate malignant from benign conditions and sometimes yield diagnosis of a malignancy. However, even when supported by immunohistochemistry, cytological interpretation can be challenging, especially if tumor cellularity is low. Here, we investigated whether targeted deep sequencing of formalin-fixed and paraffin embedded (FFPE) cytology specimens of cancer patients is feasible, and has diagnostic and clinical impact. To this end, a cohort of 20 matched pairs was compiled, each comprising a cytology sample (FFPE cell block) and at least one biopsy/surgical resection specimen serving as benchmark. In addition, 5 non-malignant effusions were sequenced serving as negative-controls. All samples yielded sufficient libraries and were successfully subjected to targeted sequencing employing a semiconductor based next-generation sequencing platform. Using gene panels of different size and composition, including the Oncomine Comprehensive Assay, for targeted sequencing, somatic mutations were detected in the tissue of all 20 cases. Of these, 15 (75%) harbored mutations that were also detected in the corresponding cytology samples. In four of these cases (20%), additional private mutations were detected in either cytology or tissue samples, reflecting spatiotemporal tumor evolution. Of the five remaining cases, three (15%) showed wild type alleles in cytology material whereas tumor tissue had mutations in interrogated genes. Two cases were discordant, showing different private mutations in the cytology and in the tissue sample, respectively. In summary, sequencing of cytology specimens (FFPE cell block) reflecting spatiotemporal tumor evolution is feasible and yields adjunct genetic information that may be exploitable for diagnostics and therapy.

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“…23 With many more drugs in the pipeline of various pharmaceutical companies, solving this issue will become increasingly important. While genetic parameters, 24 such as PD-L1 amplification, 25,26 mutational burden, [27][28][29][30][31] mutated POLE, 32,33 and microsatellite instability 34 as well as specific immune cell compositions 35 can identify patients that benefit from checkpoint blockade, recent data demonstrated that specific mutations in B2M, JAK1 and JAK2 occurring either de novo during therapy or already being present in treatment-naïve melanoma or colorectal cancer confer resistance to pembrolizumab. 36,37 Albeit the number of cases was low in both studies, these reports strongly suggest that negative response predictors are available that could directly complement stratifiers currently in use.…”

mentioning

confidence: 99%

Mutation patterns in genes encoding interferon signaling and antigen presentation: A pan‐cancer survey with implications for the use of immune checkpoint inhibitors

Budczies

Bockmayr

Klauschen

et al. 2017

Genes Chromosomes & Cancer

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Blockade of immune checkpoints has become a powerful tool in cancer medicine, which is effective across various solid cancer types and hematologic malignancies. While immunohistochemical detection of PD-L1 expression in tumor cells, immune cells, or both has been introduced as predictive biomarker in several clinical trials, shortcomings and limitations of this approach were quickly recognized. As a single biomarker is unlikely to adequately reflect the complex interplay between immune cells and cancer, various genetic determinants of therapy success, including microsatellite instability, mutational burden, and PD-L1 amplification, are being investigated. Very recent work indicates that mutations in B2M, JAK1, and JAK2 render melanoma resistant to immune checkpoint blockade, thus serving as negative response predictors. Using the TCGA dataset, we performed a pan-cancer analysis of potentially damaging mutations in key genes implicated in antigen presentation and interferon-gamma signaling and investigated associations with transcript levels of immune checkpoint genes, cytolytic activity, and mutational burden. For B2M, JAK1, and JAK2, we observed overall mutation frequencies of 1.8%, 2%, and 2.6%, respectively, and found significant associations with mutational burden. On pathway level, melanoma as well as bladder, gastric, and lung cancer were most frequently affected by putative resistance mutations with mutation rates of 27%-50% in the antigen presentation pathway and of 16%-21% in the interferon signaling pathway. Our analysis suggests that a significant number of tumors harbor mutations that may negatively interfere with immune checkpoint inhibition, or confer a higher likelihood of resistance for which a second hit is ultimately required. Since these mutations are prevalent in treatment-naïve tumors, genetic screening prior to therapy might complement current approaches at predicting response to immune checkpoint blockade.

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Classical pathology and mutational load of breast cancer – integration of two worlds

Cited by 98 publications

References 56 publications

Strong Correlation of Indoleamine 2,3-Dioxygenase 1 Expression with Basal-Like Phenotype and Increased Lymphocytic Infiltration in Triple-Negative Breast Cancer

Strong Correlation of Indoleamine 2,3-Dioxygenase 1 Expression with Basal-Like Phenotype and Increased Lymphocytic Infiltration in Triple-Negative Breast Cancer

Targeted deep sequencing of effusion cytology samples is feasible, informs spatiotemporal tumor evolution, and has clinical and diagnostic utility

Mutation patterns in genes encoding interferon signaling and antigen presentation: A pan‐cancer survey with implications for the use of immune checkpoint inhibitors

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