May 2018 Case

Authors

Eric Vail, MD (Fellow), Jean Lopategui, MD (Faculty)

Subject: Molecular Pathology
Clinical History

The patient is a 57 year old female with history of heavy second hand smoke exposure, found incidentally to have a lung nodule. Biopsy showed squamous cell carcinoma. She presented for surgical excision and management. A lobectomy and lymph node dissection was performed.

Figures

Figure 1: Gross image of lung mass, showing cavitary changes secondary to previous biopsy and measuring 2.9 cm.

Figure 2: (A) The tumor showed distinct areas of squamous cell carcinoma (~90%) and adenocarcinoma (~10%). (B) Higher power view (20x) of adenocarcinoma component. (C) Higher power view (20x) of squamous cell carcinoma component.

Figure 3: Next generation sequencing pile-ups from area of adenocarcinoma showing (A) an EGFR L858R variant at a VAF of ~20% and (B) an EGFR T790M variant at a VAF of ~50%. Sequencing of the squamous cell component showed similar results. Tumor cellularity in both areas tested was 30-40%.

Figure 4: Sanger sequencing electropherogram of an uninvolved lymph node showing an EGFR T790M variant at a VAF of ~50%.

Diagnosis

Pulmonary adenosquamous carcinoma with a somatic EGFR L858R and germline T790M

Discussion

EGFR is one of the most commonly mutated driver genes in NSCLC (10-15% of patients in the United States) with the L858R variant and exon 19 deletions encompassing almost 90% of de novo cases. These variants are concentrated in never smokers, women and people of East Asian descent but can occur outside of these populations. Both of these variants are amenable to EGFR tyrosine kinase inhibitor (TKI) therapy and patients tend to respond well until resistance is inevitably developed, usually within 12-15 months.

The most common resistance mechanism to first and second generation TKIs is the EGFR T790M variant (~50%) which can then subsequently be treated with the third generation TKI, osimertinib. This varianthas also been rarely described in both the de novo setting (1-2%) and as a germline variant, as seen in this case. Osimertinib is the treatment of choice in both of these scenarios.

Germline T790M is associated with familial lung cancer syndromes and has a lifetime lung cancer risk in never smokers of 30-50% (Background risk ~1%) often presenting with multiple primary tumors and at a later stage. Due to this, it is necessary to perform genetic counselling and screening of family members. Interestingly, almost all cases reported to date have also been associated with a concurrent somatic EGFR mutation as was also seen in this case (L858R). Why this is has yet to be elucidated, especially considering that somatic T790M variants are known to independently drive carcinogenesis.

References

1. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proceedings of the National Academy of Sciences of the United States of America. 2004 Sep 7;101(36):13306-11.
2. Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B. EGFR mutation and resistance of non–small-cell lung cancer to gefitinib. New England Journal of Medicine. 2005 Feb 24;352(8):786-92.
3. Gazdar A, Robinson L, Oliver D, Xing C, Travis WD, Soh J, Toyooka S, Watumull L, Xie Y, Kernstine K, Schiller JH. Hereditary lung cancer syndrome targets never smokers with germline EGFR gene T790M mutations. Journal of Thoracic Oncology. 2014 Apr 1;9(4):456-63.
4. Helena AY, Arcila ME, Fleischut MH, Stadler Z, Ladanyi M, Berger MF, Robson M, Riely GJ. Germline EGFR T790M mutation found in multiple members of a familial cohort. Journal of Thoracic Oncology. 2014 Apr 1;9(4):554-8.

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