During the third situation, we were unable to make a definitive determination. Other cases with acquired mutations of uncertain significance integrated two cancers with |-catenin mutations, the two of which occurred concomitantly with the EGFR T790M mutation. Fifteen posttreatment biopsies did not reveal any new mutations as assessed from the SNaPshot assay, nor MET or EGFR amplification. Two sufferers on this group had inadequate posttreatment tissue for EGFR and MET gene copy amount analyses. Between the 15 individuals without having an recognized genetic resistance mechanism, only 2 patients had stopped EGFR TKI treatment for more than two weeks in the time of biopsy. Each of the drug-resistant tumor specimens underwent routine pathological analyses, and in some instances, sizeable alterations from the predominant histology of the resistant tumors have been observed. To our surprise, 5 patients were found to have a diagnosis of smaller cell lung cancer inside their drug-resistant tumor biopsies .
All of these cases were lung adenocarcinoma ahead of EGFR TKI remedy. The transformation to SCLC at the time of clinical TKI resistance was validated by histological description examination and confirmed by expression of neuroendocrine markers . The original EGFR mutation was maintained through the histological transformation in all five instances. A single patient also acquired a PIK3CA mutation accompanying the SCLC transformation. Clinically, these five sufferers ranged inside their sickness programs. Two sufferers had reasonably indolent disorder at once after the SCLC transformation, whereas another 3 patients showed a marked progression that was reminiscent of traditional SCLC.
4 sufferers were taken care of using a classic SCLC treatment method, platinum-etoposide¨Cbased chemotherapy, which induced marked responses in 3 cases . The fourth taken care of patient had an original response to radiation Prasugrel therapy, but declined rapidly on salvage chemotherapy. Autopsy of this situation uncovered comprehensive metastatic illness inside the lung, thoracic lymph nodes, liver, and nodules along the diaphragm, all consisting totally of SCLC and all maintaining the authentic EGFR L858R mutation with no added mutations . Then again, brain metastases still retained the visual appeal of lung adenocarcinoma, steady together with the original diagnosis. In the laboratory, we observed a diverse phenotypic transformation when utilizing the H1975 lung adenocarcinoma cell line to model acquired resistance to an EGFR inhibitor.
The cell line was produced resistant for the irreversible EGFR inhibitor, PF00299804, to which it was at first delicate, as previously described . The resistant cell line didn’t obtain MET amplification, but did display an enhanced copy number with the EGFR T790M allele, consistent with preceding reports .