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Botling, Johan
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Publications (10 of 96) Show all publications
Lantuejoul, S., Sound-Tsao, M., Cooper, W. A., Girard, N., Hirsch, F. R., Roden, A. C., . . . Mino-Kenudson, M. (2020). PD-L1 Testing for Lung Cancer in 2019: Perspective From the IASLC Pathology Committee. Journal of Thoracic Oncology, 15(4), 499-519
Open this publication in new window or tab >>PD-L1 Testing for Lung Cancer in 2019: Perspective From the IASLC Pathology Committee
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2020 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 15, no 4, p. 499-519Article, review/survey (Refereed) Published
Abstract [en]

The recent development of immune checkpoint inhibitors (ICIs) has led to promising advances in the treatment of patients with NSCLC and SCLC with advanced or metastatic disease. Most ICIs target programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) axis with the aim of restoring antitumor immunity. Multiple clinical trials for ICIs have evaluated a predictive value of PD-L1 protein expression in tumor cells and tumor-infiltrating immune cells (ICs) by immunohistochemistry (IHC), for which different assays with specific IHC platforms were applied. Of those, some PD-L1 IHC assays have been validated for the prescription of the corresponding agent for first- or second-line treatment. However, not all laboratories are equipped with the dedicated platforms, and many laboratories have set up in-house or laboratory-developed tests that are more affordable than the generally expensive clinical trial-validated assays. Although PD-L1 IHC test is now deployed in most pathology laboratories, its appropriate implementation and interpretation are critical as a predictive biomarker and can be challenging owing to the multiple antibody clones and platforms or assays available and given the typically small size of samples provided. Because many articles have been published since the issue of the IASLC Atlas of PD-L1 Immunohistochemistry Testing in Lung Cancer, this review by the IASLC Pathology Committee provides updates on the indications of ICIs for lung cancer in 2019 and discusses important considerations on preanalytical, analytical, and postanalytical aspects of PD-L1 IHC testing, including specimen type, validation of assays, external quality assurance, and training.

Keywords
PD-L1, Immunohistochemistry, NSCLC, SCLC, Immunotherapy
National Category
Cancer and Oncology Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-409968 (URN)10.1016/j.jtho.2019.12.107 (DOI)000522855800014 ()31870882 (PubMedID)
Available from: 2020-05-05 Created: 2020-05-05 Last updated: 2020-05-05Bibliographically approved
Graf, W., Cashin, P., Ghanipour, L., Enblad, M., Botling, J., Terman, A. & Birgisson, H. (2020). Prognostic Impact of BRAF and KRAS Mutation in Patients with Colorectal and Appendiceal Peritoneal Metastases Scheduled for CRS and HIPEC. Annals of Surgical Oncology, 27(1), 293-300
Open this publication in new window or tab >>Prognostic Impact of BRAF and KRAS Mutation in Patients with Colorectal and Appendiceal Peritoneal Metastases Scheduled for CRS and HIPEC
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2020 (English)In: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681, Vol. 27, no 1, p. 293-300Article in journal (Refereed) Published
Abstract [en]

Background

KRAS and BRAF mutations are prognostic and predictive tools in metastatic colorectal cancer, but little is known about their prognostic value in patients scheduled for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Therefore, we analyzed the prognostic impact of KRAS and BRAF mutations in patients with peritoneal metastases scheduled for CRS and HIPEC.

Patients and Methods

In a consecutive series of 399 patients scheduled for CRS and HIPEC between 2009 and 2017, 111 subjects with peritoneal metastases from primaries of the appendix, colon, or rectum were analyzed for KRAS mutation and 92 for BRAF mutation.

Results

Mutation in KRAS was present in 51/111 (46%), and mutated BRAF was found in 10/92 (11%). There was no difference in overall survival between KRAS mutation tumors and KRAS wild type, whereas BRAF mutation was associated with short survival. No subject with BRAF mutation survived 2 years. On multivariate analysis, completeness of cytoreduction score (CCS, p = 0.000001), presence of signet cell differentiation (p = 0.000001), and BRAF mutation (p = 0.0021) were linked with poor prognosis.

Conclusions

BRAF mutation is a marker of poor prognosis in patients with appendiceal and colorectal peritoneal metastases scheduled for CRS and HIPEC, whereas survival outcome in subjects with mutated KRAS does not differ from wild-type KRAS. This finding suggests that those with BRAF mutation should be considered for alternative treatment options.

National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-408132 (URN)10.1245/s10434-019-07452-2 (DOI)000489509800003 ()31571052 (PubMedID)
Funder
Swedish Cancer Society, 150767
Available from: 2020-04-07 Created: 2020-04-07 Last updated: 2020-04-07Bibliographically approved
Biswas, D., Birkbak, N. J., Rosenthal, R., Hiley, C. T., Lim, E. L., Papp, K., . . . Swanton, C. (2019). A clonal expression biomarker associates with lung cancer mortality. Nature Medicine, 25(10), 1540-1548
Open this publication in new window or tab >>A clonal expression biomarker associates with lung cancer mortality
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2019 (English)In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 25, no 10, p. 1540-1548Article in journal (Refereed) Published
Abstract [en]

An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage(1). Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types(2-6). Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types.

National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-396656 (URN)10.1038/s41591-019-0595-z (DOI)000489166700023 ()31591602 (PubMedID)
Funder
EU, European Research Council, FP7-THESEUS-617844EU, European Research Council, 835297
Available from: 2019-11-14 Created: 2019-11-14 Last updated: 2020-01-08Bibliographically approved
Tsakonas, G., Botling, J., Micke, P., Rivard, C., La Fleur, L., Mattsson, J. S., . . . Ekman, S. (2019). c-MET as a biomarker in patients with surgically resected non-small cell lung cancer. Lung Cancer, 133, 69-74
Open this publication in new window or tab >>c-MET as a biomarker in patients with surgically resected non-small cell lung cancer
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2019 (English)In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 133, p. 69-74Article in journal (Refereed) Published
Abstract [en]

Background: c-MET protein overexpression has been proposed as a biomarker in non-small cell lung cancer (NSCLC), albeit its role in the clinical setting has not been firmly established yet. Patients and methods: We designed a retrospective cohort study, consisting of 725 patients with surgically removed NSCLC. Immunohistochemistry (IHC) was conducted in tissue microarrays (TMA) from lung tumors and healthy tissue. IHC staining was quantified using H-scores (range 0-300). Association between c-MET H-score and overall survival (OS) as well as progression-free survival (PFS) was explored. Results: c-MET H-score >= 20 had a significant positive impact on OS in the multivariate analysis in the whole study population, HR = 0.79 (95%CI: 0.64 - 0.97). The prognostic effect of c-MET H-score >= 20 was even stronger in patients who received adjuvant treatment with a HR = 0.61 (95% CI: 0.40 - 0.93). In the subgroup of adenocarcinoma and squamous cell carcinoma patients with stage IIA-IIIB disease, the prognostic impact of c-MET was significant in the univariate analysis (HR = 0.60, 95% CI: 0.43 - 0.83). Conclusion: c-MET H-score >= 20 is a positive prognostic biomarker for OS in early stage NSCLC. This benefit seems to be strongly correlated to adjuvant chemotherapy, therefore rendering c-MET H-score >= 20 a possible predictive biomarker for platinum-based adjuvant chemotherapy in early stage NSCLC.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
c-MET, Lung cancer, Biomarker, OS, PFS, H-score
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-390909 (URN)10.1016/j.lungcan.2019.04.028 (DOI)000474326700012 ()31200831 (PubMedID)
Funder
Stockholm County Council
Available from: 2019-08-16 Created: 2019-08-16 Last updated: 2020-01-08Bibliographically approved
Botling, J., Lamarca, A., Bajic, D., Norlén, O., Lönngren, V., Kjaer, J., . . . Crona, J. (2019). High-grade progression confers poor survival in pancreatic neuroendocrine tumors.. Neuroendocrinology
Open this publication in new window or tab >>High-grade progression confers poor survival in pancreatic neuroendocrine tumors.
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2019 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194Article in journal (Refereed) Epub ahead of print
Abstract [en]

INTRODUCTION: Little is known about how Pancreatic Neuroendocrine Tumors (PanNETs) evolve over time and if changes towards a more aggressive biology correlates with prognosis. The purpose of this study was to characterize changes PanNET differentiation and proliferation over time, and to correlate findings to overall survival (OS).

PATIENTS AND METHODS: In this retrospective cohort study we screened 475 PanNET patients treated at Uppsala University Hospital, Sweden. Sporadic patients with baseline and follow-up tumor samples were included. Pathology reports and available tissue sections were re-evaluated with regard to tumor histopathology and Ki-67 index.

RESULTS: Forty-six patients with 106 tumor samples (56 available for pathology re-evaluation) were included. Median Ki-67 index at diagnosis was 7% (range 1-38%), grade 1 n=8, grade 2 n=36, and grade 3 n=2. The median change in Ki-67 index (absolute value; follow-up - baseline) was +14% (range -11 to +80%). Increase in tumor grade occurred in 28 patients (63.6%), the majority from grade 1/2 to grade 3 (n=24, 54.5%). The patients with a high-grade progression had a median OS of 50.2 months compared to 115.1 months in patients without such progression (HR 3.89, 95% CI 1.91-7.94, P<0.001).

CONCLUSIONS: A longitudinal increase in Ki-67 index and increase in tumor grade were observed in a majority of PanNETs included in this study. We propose that increase in Ki-67 index and high-grade progression should be investigated further as important biomarkers in PanNET.

National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Oncology; Pathology
Identifiers
urn:nbn:se:uu:diva-399943 (URN)10.1159/000504392 (DOI)31658459 (PubMedID)
Available from: 2019-12-17 Created: 2019-12-17 Last updated: 2020-02-05Bibliographically approved
Vidarsdottir, H., Tran, L., Nodin, B., Jirström, K., Planck, M., Jönsson, P., . . . Brunnström, H. (2019). Immunohistochemical profiles in primary lung cancers and epithelial pulmonary metastases. Human Pathology, 84, 221-230
Open this publication in new window or tab >>Immunohistochemical profiles in primary lung cancers and epithelial pulmonary metastases
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2019 (English)In: Human Pathology, ISSN 0046-8177, E-ISSN 1532-8392, Vol. 84, p. 221-230Article in journal (Refereed) Published
Abstract [en]

Correct diagnosis of pulmonary tumors is essential for treatment decision and often rely on immunohistochemical markers. We stained tissue microarrays from resected primary lung cancer (n=665) and pulmonary metastases (n=425) for CK7, CK20, CDX2, CK5, p40, p63, TTF-1, napsin A, GATA3 and PAX8 to systematically assess the diagnostic value of these markers. Primary lung adenocarcinomas expressed TTF-1 in 90% and napsin A in 84% of the cases, while 10% were positive for p63, 7% for CDX2, 2% for CK20 and 2% for GATA3. Only 68% of the lung adenocarcinomas were positive for CK7, TTF-1 and napsin A and negative for all other markers. Primary lung squamous cell carcinomas expressed CK5, p40 and p63 in 94-97% of cases, while 44% were positive for CK7, 20% for GATA3, 7% for CDX2 and 3% for TTF-1. Rare cases expressed PAX8, CK20 or napsin A. Pulmonary metastases of colorectal cancer were positive for CK20 in 83% and CDX2 in 99% of the cases. Rare cases expressed CK7, p63 or PAX8, while 4% expressed TTF-1. Pulmonary metastases of renal cell carcinomas were positive for PAX8 in 74%, napsin A in 7% and CK7 in 7% of the cases. Pulmonary metastases of breast cancer were positive for GATA3 in 93% and CK7 in 78% of the cases, while 15% expressed CK5. Information on expression and patterns of immunohistochemical markers facilitates histopathological diagnostics. Evidently, unusual immune profiles occur and may lead to incorrect diagnosis.

Keywords
CDX2, Cytokeratin, GATA3, Napsin a, TTF-1, Tissue Microarray
National Category
Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-372013 (URN)10.1016/j.humpath.2018.10.009 (DOI)000461725100025 ()30389437 (PubMedID)
Available from: 2019-01-04 Created: 2019-01-04 Last updated: 2020-01-03Bibliographically approved
Micke, P., Botling, J., Mattsson, J. S., Planck, M., Tran, L., Vidarsdottir, H., . . . Brunnstrom, H. (2019). Mucin staining is of limited value in addition to basic immunohistochemical analyses in the diagnostics of non-small cell lung cancer. Scientific Reports, 9, Article ID 1319.
Open this publication in new window or tab >>Mucin staining is of limited value in addition to basic immunohistochemical analyses in the diagnostics of non-small cell lung cancer
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 1319Article in journal (Refereed) Published
Abstract [en]

Accurate diagnosis of histological type is important for therapy selection in lung cancer. Immunohistochemical (IHC) and histochemical stains are often used to complement morphology for definite diagnosis and are incorporated in the WHO classification. Our main aim was to compare different mucin stains and assess their value in relation to common IHC analyses in lung cancer diagnostics. Using tissue microarrays from 657 surgically treated primary lung cancers, we evaluated the mucin stains periodic acid-Schiff with diastase (PASD), alcian blue-periodic acid-Schiff (ABPAS) and mucicarmine, and compared with the IHC markers p40, p63, cytokeratin 5, thyroid transcription factor 1 (TTF-1), napsin A and cytokeratin 7. Ten or more cytoplasmic mucin inclusions in a tissue microarray core were seen in 51%, 48% and 31% of the 416 adenocarcinomas and 3%, 4% and 0.5% of the 194 squamous cell carcinomas with PASD, ABPAS and mucicarmine, respectively. Diagnostic pitfalls, such as entrapped benign epithelium, apoptotic/necrotic cells and glycogen, partly differed for the mucin stains. TTF-1 and napsin A IHC stainings had similar specificity but better sensitivity for adenocarcinoma than the mucin stains, but addition of PASD or ABPAS identified more tumors as adenocarcinomas (n = 8 and n = 10, respectively) than napsin A (n = 1) in cases with solid growth that were negative for TTF-1 and p40. We conclude that PASD and ABPAS have similar diagnostic performance and that these markers are of value in poorly differentiated cases. However, morphology and TTF-1 and p40 IHC staining is sufficient for correct diagnosis in most non-small cell lung cancers.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Cancer and Oncology Cell and Molecular Biology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-377598 (URN)10.1038/s41598-018-37722-0 (DOI)000457616300207 ()30718697 (PubMedID)
Available from: 2019-02-26 Created: 2019-02-26 Last updated: 2020-01-03Bibliographically approved
La Fleur, L., Falk-Sörqvist, E., Smeds, P., Berglund, A., Sundström, M., Mattsson, J. S., . . . Botling, J. (2019). Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11. Lung Cancer, 130, 50-58
Open this publication in new window or tab >>Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11
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2019 (English)In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 130, p. 50-58Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Non-small cell lung cancer (NSCLC) is a heterogeneous disease with unique combinations of somatic molecular alterations in individual patients, as well as significant differences in populations across the world with regard to mutation spectra and mutation frequencies. Here we aim to describe mutational patterns and linked clinical parameters in a population-based NSCLC cohort.

MATERIALS AND METHODS: Using targeted resequencing the mutational status of 82 genes was evaluated in a consecutive Swedish surgical NSCLC cohort, consisting of 352 patient samples from either fresh frozen or formalin fixed paraffin embedded (FFPE) tissues. The panel covers all exons of the 82 genes and utilizes reduced target fragment length and two-strand capture making it compatible with degraded FFPE samples.

RESULTS: We obtained a uniform sequencing coverage and mutation load across the fresh frozen and FFPE samples by adaption of sequencing depth and bioinformatic pipeline, thereby avoiding a technical bias between these two sample types. At large, the mutation frequencies resembled the frequencies seen in other western populations, except for a high frequency of KRAS hotspot mutations (43%) in adenocarcinoma patients. Worse overall survival was observed for adenocarcinoma patients with a mutation in either TP53, STK11 or SMARCA4. In the adenocarcinoma KRAS-mutated group poor survival appeared to be linked to concomitant TP53 or STK11 mutations, and not to KRAS mutation as a single aberration. Similar results were seen in the analysis of publicly available data from the cBioPortal. In squamous cell carcinoma a worse prognosis could be observed for patients with MLL2 mutations, while CSMD3 mutations were linked to a better prognosis.

CONCLUSION: Here we have evaluated the mutational status of a NSCLC cohort. We could not confirm any survival impact of isolated driver mutations. Instead, concurrent mutations in TP53 and STK11 were shown to confer poor survival in the KRAS-positive adenocarcinoma subgroup.

Keywords
KRAS, Mutation patterns, Non-small cell lung cancer, STK11, TP53, Targeted resequencing
National Category
Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-380587 (URN)10.1016/j.lungcan.2019.01.003 (DOI)000463276900008 ()30885352 (PubMedID)
Funder
Swedish Cancer Society, 2013/711Swedish Cancer Society, 2016/827
Available from: 2019-03-29 Created: 2019-03-29 Last updated: 2020-01-03Bibliographically approved
Salomonsson, A., Patthey, A., Reutersward, C., Jonsson, M., Botling, J., Brunnstrom, H., . . . Planck, M. (2018). A Nation-Wide Population-Based Mapping of Targetable Alterations in Smoking-Independent Lung Cancer. Paper presented at IASLC 19th World Conference on Lung Cancer. Journal of Thoracic Oncology, 13(10), S431-S432
Open this publication in new window or tab >>A Nation-Wide Population-Based Mapping of Targetable Alterations in Smoking-Independent Lung Cancer
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2018 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, no 10, p. S431-S432Article in journal, Meeting abstract (Other academic) Published
Keywords
population-based, never-smoker, gene fusion
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-373922 (URN)10.1016/j.jtho.2018.08.497 (DOI)000454014501133 ()
Conference
IASLC 19th World Conference on Lung Cancer
Available from: 2019-01-17 Created: 2019-01-17 Last updated: 2019-01-17Bibliographically approved
Vidarsdottir, H., Tran, L., Nodin, B., Jirström, K., Planck, M., Mattsson, J. S., . . . Brunnström, H. (2018). Comparison of Three Different TTF-1 Clones in Resected Primary Lung Cancer and Epithelial Pulmonary Metastase. American Journal of Clinical Pathology, 150(6), 533-544
Open this publication in new window or tab >>Comparison of Three Different TTF-1 Clones in Resected Primary Lung Cancer and Epithelial Pulmonary Metastase
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2018 (English)In: American Journal of Clinical Pathology, ISSN 0002-9173, E-ISSN 1943-7722, Vol. 150, no 6, p. 533-544Article in journal (Refereed) Published
Abstract [en]

Objectives: Immunohistochemical staining against thyroid transcription factor 1 (TTF-1) is often used to distinguish lung adenocarcinoma from squamous cell carcinoma and pulmonary metastasis.

Methods: TTF-1 expression was examined using the antibody clones 8G7G3/1, SPT24, and SP141 on tissue microarrays from 665 cases of resected lung cancers and 428 pulmonary metastases.

Results: Most lung adenocarcinomas, 89%, 93%, and 93%, were positive with TTF-1 clones 8G7G3/1, SPT24, and SP141, respectively. The corresponding figures for lung squamous cell carcinomas were 0%, 6%, and 8%. In total, five (2%), 19 (7%), and 21 (8%) of the pulmonary metastases from colorectal adenocarcinomas were positive with clones 8G7G3/1, SPT24, and SP141, respectively. Other TTF-1-positive pulmonary metastases (n = 8) were thyroid, urothelial, pancreatic, small bowel, and cervix carcinomas.

Conclusions: TTF-1 expression in lung cancer and pulmonary metastases differs between clones, with 8G7G3/1 being more specific but less sensitive compared with SPT24 and SP141.

National Category
Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-372014 (URN)10.1093/ajcp/aqy083 (DOI)000456564300008 ()30169783 (PubMedID)
Available from: 2019-01-04 Created: 2019-01-04 Last updated: 2019-03-29Bibliographically approved
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