A 61-year-old female patient with no personal medical history except osteoporosis and no familial history of cancer; former smoker estimated at 2 packs/year presented in May 2022 severe and rapid deterioration in general condition resulting in severe asthenia associated with complete anorexia, nausea and epigastric pain. Clinical examination revealed a painful hepatomegaly without other clinical abnormality, and hepatic sonogram showed diffuse bilobar lesions.
On June 7, a computerized tomography (CT) scan showed diffuse hepatic lesions associated with multiple sus and sub-diaphragmatic lymphadenopathies, pleural effusion, diffuse bone and pulmonary lesions.
On June 15, a liver biopsy led to the diagnosis of a CK7+; CK20-; TTF1+; SATB2-; GATA 3- mucus-secreting carcinoma leading to the diagnosis of T1aN3M1c bronchopulmonary adenocarcinoma according to the 8th version of the TNM classification. Blood tests on June 17 revealed anemia with hemoglobin at 7.5 g/dL; international normalized ratio (INR) increase at 1.51; hepatic enzymes increase with gamma-glutamyltransferase at 458 U/L; alkaline phosphatase at 703 U/L; aspartate aminotransferase at 156 U/L; alanine aminotransferase at 129 U/L; total and conjugated bilirubin increase at respectively 56.9 micromol/L and 32.6 micromol/L. The suspicion of acute liver failure led to her hospitalization. Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 3, oxygen was needed at 1-2 L/min. Viral serologies were negatives (Hepatitis B, Hepatitis C, HIV, Cytomegalovirus), there were no history of alcoholic intoxication or recent introduction of new medication explaining the hepatic perturbations. Treatment was initially postponed waiting for the results of tumor molecular biology, considering the high probability of an oncogenic driver for this patient former smoker under 5 packs/year. A liquid biopsy was realized on June 21 to research ctDNA alterations.
On June 22, following to appearance of encephalopathy due to hepatic failure it was decided to initiate salvage chemotherapy with weekly paclitaxel/carboplatin regimen. After 48 hours, the patient developed a massive hematoma in front of central venous catheter associated with clinical degradation and increase of oxygen need to 4 L/min. Blood tests revealed grade 3 according to common terminology criteria for adverse events v5.0 (CTCAE v5.0) platelet count decrease leading to an initial diagnosis of disseminated intravascular coagulation. Subsequent analysis revealed anemia, negative haptoglobin, and schizocytes on blood smear, rectifying the diagnosis of paraneoplastic thrombotic microangiopathy. A new CT-scan showed massive pleural and peritoneal effusion. This dramatic clinical and biological deterioration resulted in stopping antitumor treatment and focusing on best supportive care.
However, on June 27, the results of ctDNA performed on June 21 by digital droplet PCR (ddPCR) revealed the presence of an EGFR DEL19 mutation with very high amount of copies (736,400 per mL of plasma). A last-ditch attempt was decided by initiating a TKI treatment with osimertinib 80 mg per day, first dose received on June 28 ( Figure 1 ).
After one week of treatment, a clinical and biological improvement was observed with decrease of oxygen requirement, edemas, lactate dehydrogenase and INR. On July 4, a control of ctDNA showed a drastic drop to 3,763 copies of mutated DNA/mL of plasma. A second control was performed on July 12, finding 6,377 copies/mL for EGFR DEL19 and a possible EGFR T790M resistance mutation at 4.0 copies/mL ( Figure 1 ).
Clinically, oxygen was stopped on July 8, after 10 days of treatment with osimertinib. Molecular alterations were also investigated on the hepatic punctured tissue: the results came out on July 7. The NGS performed on tissue biopsy confirmed the presence of an EGFR DEL 19 with a variant allele frequency of 88.45%. The NGS experiment also revealed the presence of an EGFR amplification with 10 copies of genes and a Janus Kinase 3 (JAK3) amplification with 14 copies of genes.
After three weeks of treatment by osimertinib associated with supportive care, the patient was able to return directly to her home without requiring a rehabilitation. After 2 months of treatment with osimertinib, the patient was clinically asymptomatic and has no side effects from the TKI. The CT-scan performed shows a partial morphological response according to RECIST1.1 criteria ( Figure 2 ). Control of ctDNA rate revealed a residual value for the EGFR DEL19 activating mutation (40.0 copies/mL) and the disappearance of the EGFR T790M mutation ( Figure 1 ).
To date, after 5 months of full-dose treatment with osimertinib 80mg/day, the patient still has an excellent tolerance of the treatment with maintained efficacy.