PMC9868143_01
Representative clinical images during the treatment course. (A) Disease time line showed the various treatment received by the patient and her clinical response. (B) Chest-CT scans showed the disease progression under treatment.
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I (pT1cN0M0) primary breast cancer, which was surgically removed, and stage IVA (cT4N0M1a) primary lung adenocarcinoma (LUAD) in October 2015 (Figure 1A). Immunohistochemistry (IHC) staining of the resected breast tumor tissue was positive for estrogen receptor (ER, 50%), progesterone receptor (PR, 70%) and human epidermal growth factor 2 (HER2) and negative for Cytokeratin 5/6 (CK 5/6), P53, Topoisomerase I (TOPO I) and EGFR. December 2015, two cycles of chemotherapy with pemetrexed (0.8 g on d3) and cisplatin (50 mg on d1, 40 mg on d2,3) were administered for the treatment of LUAD (Figure 1B). Due to a positive result of sanger sequencing for exon 21 mutation (p.L861Q) and a rare EGFR exon 20 mutation (p.R776H), the patient was subsequently given Gefitinib (250 mg once daily), the first-generation EGFR TKI, in January 2016. The patient exhibited a stable disease (SD) (Figure 1B) and continued to be treated with Gefitinib until December 2017. At that time, the patient developed progressive disease (PD) with an enlarged primary lung tumor (Figure 1B). Two months later, the lung lesion increased again indicating PD (Figure 1B).   Six months post treatment, CT scans revealed no marked enlargement of the lesion indicating an SD (Figure 1B). In December 2018, the patient suffered from headache and CT scans revealed the lung lesions increased with pleural effusion, thus indicating PD (Figure 1B).
Hematoxylin & eosin (HE) and immunohistochemical (IHC) staining for the breast tumor tissue and the right lung tumor biopsy. (A) HE staining (200x) of the primary breast cancer. (B-E) IHC examinations (200x) of the breast tumor tissue was positive for estrogen receptor (ER, 50%), progesterone receptor (PR, 70%) and human epidermal growth factor 2 (HER2). The ki67 index was 15%. (F) HE staining (200x) of the primary lung adenocarcinoma. (G and H) IHC staining (200x) of the right lung tumor biopsy showed positive staining for TTF-1 and Napsin A.
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Ki67 labeling in the tumor cells was 15% (Figure 2A-E). IHC analysis of a right lung tumor biopsy showed positive staining for LUAD markers, TTF-1 and Napsin A (Figure 2F-H), which confirming the primary LUAD.
Pedigree of the proband's family. Squares and circles denote males and females, respectively. Roman numerals indicate generations. The proband was marked with an arrow. A small red circle indicates which family members were tested and found to carry EGFR R776H. A small hollow circle indicates which family members were tested and found not to carry EGFR R776H. The numbers after cancer sites indicate the age at diagnosis. The age of death is marked if known.
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Genetic testing revealed another three carriers of EGFR R776H aside from the proband, two elder sisters and her younger sister with lung cancer without her daughter (Figure 3).