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Yasushi YATABE
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EP1.14 - Targeted Therapy (ID 204)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.14-44 - Lung Adenocarcinoma with a Rare BRAF V600E K601_W604del Mutation Responded to Dabrafenib Plus Trametinib Treatment: A Case Report (Now Available) (ID 1485)
08:00 - 18:00 | Author(s): Yasushi YATABE
- Abstract
Background
BRAF V600E mutation can be detected in 1% of lung adenocarcinomas, and far more rarely, complex mutations in addition to BRAF V600E have been reported.
Method
Case presentation: A 42-year-old man was diagnosed with advanced lung adenocarcinoma with stage cT1cN3M1c stageIVB. BRAF V600E mutation was found with in-house molecular testing, so we submitted the same specimen to be analyzed with Oncomine Dx Target test for reimbursement of the subsequent treatment. However, the result was negative for BRAF V600E.
Result
The patient was treated with pembrolizumab (first-line therapy) and then carboplatin, pemetrexed and bevacizumab (second-line therapy). Nevertheless, the disease was progressed, so dabrafenib plus trametinib were used for the third line therapy. One month later CT scan showed a partial response. A subsequent study showed that the V600E mutation accompanied K601_W604 deletion, three bases after the V600E point mutation.
Conclusion
Our clinical experience suggested that some tumors with compound BRAF mutations, such as BRAF V600E K601_W604 del mutation, could respond to dabrafenib plus trametinib treatment, and that rare compound mutations, like this case, may not be detected with the conventional amplicon sequencing, particularly when the additional alterations are acquired at the positions adjacent to hotspots.
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ES12 - Lung Cancer Pathology in the Age of Genomics (ID 15)
- Event: WCLC 2019
- Type: Educational Session
- Track: Pathology
- Presentations: 1
- Now Available
- Moderators:Masayuki Noguchi, Beatriz Bellosillo
- Coordinates: 9/08/2019, 15:15 - 16:45, Toronto (1985)
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ES12.02 - Invasive Mucinous Adenocarcinoma (Now Available) (ID 3219)
15:15 - 16:45 | Presenting Author(s): Yasushi YATABE
- Abstract
- Presentation
Abstract
Invasive mucinous adenocarcinoma (IMA) is a variant of adenocarcinoma defined by the current WHO classification of lung tumors.1 Although IMA used to be categorized into mucinous bronchioloalveolar carcinoma in most cases with the previous classification scheme,2 separation of this variant was based on unique clinical, radiological, pathological, and genetic characteristics as shown in the following table. Morphologically, IMAs consist of goblet and/or columnar tumor cells, which resemble normal intestinal and/or primitive gut epithelium. This subtype adenocarcinoma develops not only in the lung but also in every organ system, such as the ovary, pancreas, colorectum, and stomach, which are associated with the primitive gut tube in development. Interesting, all mucinous carcinomas have frequent KRAS mutations and quite similar immunohistochemical phenotype, including expression of CK20, CDX2, HNF4a, and villin. The strong correlation between KRAS mutations and heavy smokers is known, but IMA is not such a case. Indeed, TP53 mutations, which is also associated more with smokers, are quite rare in IMAs. IMA commonly develops in the peripheral lung parenchyma, but there are no normal counterpart cells. Recently, inactivating mutations of TTF1/NKX2.1 have been reported in IMA.3, 4 This alteration can repress TTF1 function, resulting in gastrointestinal differentiation. TTF1-depletion using KRASG12D-transgenic mice induced mucinous tumors, which shared a morphological and phenotypical resemblance to IMA, including columnar tumor cells with goblet cell features and HNF4a expression.5, 6 Because the other mechanisms of TTF1 impairment, the molecular pathway of IMA could be summarized in figure 1. However, it remains unclear why KRAS is selectively mutated in this subtype, and what induce TTF1 mutations.
References
1. Travis WD, Brambilla E, Burke A, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: International Agency for Research on Cancer; 2015.
2. Travis WD, Brambilla E, Noguchi M, et al. International Association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244-285.
3. Matsubara D, Soda M, Yoshimoto T, et al. Inactivating mutations and hypermethylation of the NKX2-1/TTF-1 gene in non-terminal respiratory unit-type lung adenocarcinomas. Cancer science 2017;108:1888-1896.
4. Hwang DH, Sholl LM, Rojas-Rudilla V, et al. KRAS and NKX2-1 Mutations in Invasive Mucinous Adenocarcinoma of the Lung. J Thorac Oncol 2016;11:496-503.
5. Maeda Y, Tsuchiya T, Hao H, et al. Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung. J Clin Invest 2012;122:4388-4400.
6. Snyder EL, Watanabe H, Magendantz M, et al. Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma. Mol Cell 2013;50:185-199.Table 1 Difference between IMA and AIS/MIA/LPA1
Table 1 Difference between IMA and AIS/MIA/LPA Invasive Mucinous ADC
AIS/MIA/LPA
Female
~60%
~70%
Smoker
~45%
~46%
Clinical symptoms
Mucinous sputa
Mostly no symptom
Radiographic appearance
Majority consolidation; Air-bronchogram
Majority ground-glass attenuation
Frequent multifocal & multi-lobar presentation
Cell type
Mucin-filled, columnar and/or goblet
Type II pneumocyte &/or Clara cell
Phenotype
CK7
Mostly positive (90%)
Positive (~95%)
CK20
Positive (~54%)
Negative (<5%)
TTF1
Mostly negative (<10%)
Positive (~65%)
CDX2
Possible to be positive
Negative
Genotype
KRAS
Frequent (~75%)
Some (~15%)
EGFR
Almost none (<5%)
Frequent (~45%)
AIS, adenocarcinoma in situ; MIA, minimally invasive adenocarcinoma; LPA, lepidic predominant adenocarcinoma
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P2.09 - Pathology (ID 174)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.09-24 - IASLC Global Survey for Pathologists on PD-L1 Testing for Non-Small Cell Lung Cancer (ID 906)
10:15 - 18:15 | Author(s): Yasushi YATABE
- Abstract
Background
PD-L1 immunohistochemistry (IHC) is now performed for advanced non-small cell lung cancer (NSCLC) patients to examine their eligibility for pembrolizumab treatment, as well as in Europe for durvalumab therapy after chemoradiation for stage III NSCLC patients. Four PD-L1 clinical trial validated assays (commercial assays) have been FDA/EMA approved or are in vitro diagnostic tests in multiple countries, but high running costs have limited their use; thus, many laboratories utilize laboratory-developed tests (LDTs). Overall, the PD-L1 testing seems to be diversely implemented across different countries as well as across different laboratories.
Method
The Immune biomarker working group of the IASLC international pathology panel conducted an international online survey for pathologists on PD-L1 IHC testing for NSCLC patients from 2/1/2019 to 5/31/2019. The goal of the survey was to assess the current prevalence and practice of the PD-L1 testing and to identify issues to improve the practice globally. The survey included more than 20 questions on pre-analytical, analytical and post-analytical aspects of the PDL1 IHC testing, including the availability/type of PD-L1 IHC assay(s) as well as the attendance at a training course(s) and participation in a quality assurance program(s).
Result
344 pathologists from 310 institutions in 64 countries participated in the survey. Of those, 38% were from Europe (France 13%), 23% from North America (US 17%) and 17% from Asia. 53% practice thoracic pathology and 36%, cytopathology. 11 pathologists from 10 countries do not perform PD-L1 IHC and 7.6% send out to outside facility. Cell blocks are used by 75% of the participants and cytology smear by 9.9% along with biopsies and surgical specimens. Pre-analytical conditions are not recorded in 45% of the institutions. Clone 22C3 is the most frequently used (61.5%) (59% with the commercial assay; 41% with LDT) followed by clone SP263 (45%) (71% with the commercial assay; 29% with LDT). Overall, one or several LDTs are used by 57% of the participants. A half of the participants reported turnaround time as 2 days or less, while 13% reported it as 5 days or more. Importantly, 20% of the participants reported no quality assessment, 15%, no formal training session for PD-L1interpretation and 14%, no standardized reporting system.
Conclusion
There is marked heterogeneity in PD-L1 testing practice across individual laboratories. In addition, the significant minority reported a lack of quality assurance, formal training and/or standardized reporting system that need to be established to improve the PD-L1 testing practice globally.
