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Two Cases of Small Cell Lung Cancer Transformation from EGFR Mutant Adenocarcinoma During AZD9291 Treatment

      Case 1

      A stage IVA lung adenocarcinoma (cT3N2M1a) harboring an epidermal growth factor receptor gene (EGFR) mutation in exon 21 (L858R) was diagnosed in a 57-year-old woman, a never-smoker. The patient was treated with erlotinib for 12 months and then with cisplatin plus pemetrexed followed by pemetrexed for 8 months. At the time of progression, a repeat biopsy showed a T790M missense mutation in exon 20 accompanied by an L858R mutation. The patient participated in a phase I clinical trial of AZD9291 and was treated with a dose of 160 mg. Notable shrinkage of her lung mass was observed after two cycles of AZD9291, and this response continued for 14 months. Eventually, she experienced rapid progression of the disease along with aggravation of her symptoms, including cough and dyspnea. A repeat biopsy was performed because of the rapid progression, and histologic analysis of her lung mass showed small cell lung cancer (SCLC) that immunohistochemical staining confirmed as positive for CD56 (Fig. 1). Intriguingly, a next-generation sequence showed persistence of the L858R mutation and EGFR gene amplification but loss of the T790M mutation (Fig. 2 and Supplemental Fig. 1). After two cycles of etoposide and carboplatin, the patient's tumor was markedly smaller on a follow-up chest computed tomography scan (Fig. 3) and her respiratory symptoms also improved.
      Figure thumbnail gr1
      Figure 1(A) Tissue section from the pleura of the patient in case 1 (hematoxylin and eosin stain, magnification ×400) that was obtained before AZD9291 treatment and shows metastatic adenocarcinoma. (B) Tissue section obtained from a lung of the patient in case 1 and showing small cell carcinoma (hematoxylin and eosin stain, magnification ×400). (C) Tissue sample from the same lung (CD56 immunohistochemical stain, magnification ×400); CD56-positive staining was obtained when the patient's disease progressed while she was receiving AZD9291 for 14 months. (D) Tissue section from a lung of the patient in case 2 (hematoxylin and eosin stain, magnification ×400) that was obtained before AZD9291 treatment and shows adenocarcinoma. (E) Tissue section from a lung of the patient in case 2 showing small cell carcinoma (hematoxylin and eosin stain, magnification ×400). (F) Tissue section from the same lung (CD56 immunohistochemical stain, magnification ×400); CD56-positive staining was obtained when the patient's disease progressed while she was being given AZD9291 for 18 months.
      Figure thumbnail gr2
      Figure 2In case 1, a next-generation sequence showed persistence of the L858R mutation (B) but loss of the T790M mutation (A). In case 2, a next-generation sequence showed persistence of the exon 19 deletion (C) but loss of the T790M mutation (A).
      Figure thumbnail gr3
      Figure 3Computed tomography (CT) scans of the patient in case 1. (A) CT scan before AZD9291 treatment. Multiple pleural nodules and a para-aortic lymph node were noted. (B) CT scan after 2 months of AZD9291 treatment. The extent of the pleural nodules and para-aortic lymph node was decreased. (C) CT scan after 14 months of AZD9291 treatment. A huge left upper lobe and hilar masses were noted. (D) CT scan after two cycles of etoposide and carboplatin chemotherapy. The huge masses were markedly smaller.

      Case 2

      Recurrent lung adenocarcinoma with lung-to-lung metastasis developed in a 58-year-old woman, a never-smoker, 2 years after she had undergone curative surgery. Direct sequencing of her tumor showed EGFR wild-type disease. The patient was treated with erlotinib for 24 months as second-line therapy followed by afatinib for 9 months. At the time of disease progression, a repeat biopsy showed an exon 19 deletion along with a T790M mutation. The patient also participated in a phase I clinical trial of AZD9291 and was treated with a dose of 80 mg. Her disease progressed after 18 months of treatment, and a repeat biopsy specimen showed SCLC (see Fig. 1). The next-generation sequence showed loss of the T790M mutation but presence of an exon 19 deletion (see Fig. 2 and Supplemental Fig. 1). The patient also achieved a partial response to etoposide and carboplatin combination therapy (Supplemental Fig. 2).

      Discussion

      SCLC transformation is one of the resistance mechanisms associated with treatment with first-generation EGFR tyrosine kinase inhibitors (TKIs), accounting for 10% of cases.
      • Sequist L.V.
      • Waltman B.A.
      • Dias-Santagata D.
      • et al.
      Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.
      • Oser M.G.
      • Niederst M.J.
      • Sequist L.V.
      • et al.
      Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin.
      AZD9291 (AstraZeneca) is an oral irreversible EGFR TKI with selectivity for activating EGFR mutations and the T790M resistance mutation.
      • Cross D.A.
      • Ashton S.E.
      • Ghiorghiu S.
      • et al.
      AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.
      A recent phase I clinical study demonstrated that AZD9291 resulted in a response rate of 51% and progression-free survival time of 9.6 months in EGFR T790M–positive patients in whom resistance to previous EGFR TKIs had developed.
      • Janne P.A.
      • Yang J.C.
      • Kim D.W.
      • et al.
      AZD9291 in EGFR inhibitor–resistant non–small-cell lung cancer.
      However, patients treated with third-generation EGFR TKIs experience progression eventually. Recently, two cases of SCLC transformation during treatment with the third-generation EGFR TKI rociletinib were reported as being characterized by a resistance mechanism
      • Piotrowska Z.
      • Niederst M.J.
      • Karlovich C.A.
      • et al.
      Heterogeneity underlies the emergence of EGFRT790 wild-type clones following treatment of T790M-positive cancers with a third-generation EGFR inhibitor.
      that had not yet been described during treatment with AZD9291. Acquired EGFR C797S mutation was thought to be one of the resistance mechanisms associated with AZD9291 treatment.
      • Thress K.S.
      • Paweletz C.P.
      • Felip E.
      • et al.
      Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M.
      The two cases are the first reported cases of SCLC transformation during treatment with AZD9291. Genomic study showed loss of the T790M mutation in the presence of a preexisting EGFR mutation. We did not find any abnormalities of retinoblastoma (RB) genes in either case. These results suggest that repeat biopsy is also essential for patients whose disease progresses while they are receiving a third-generation EGFR TKI so that an appropriate treatment decision can be made according to the diverse mechanisms of acquired resistance. In the case of SCLC transformation, a favorable response to combination chemotherapy with agents such as etoposide and platinum can be expected.

      Supplementary Data

      Figure thumbnail figs1
      Supplemental Figure 1Computed tomography (CT) scans of the patient in case 2. (A) CT scan before AZD9291 treatment. Multiple lung nodules and masses were noted. (B) CT scan after 2 months of AZD9291 treatment. The extent of the multiple lung nodules and masses was decreased. (C) CT scan after 18 months of AZD9291 treatment. The multiple lung nodules were increased. (D) CT scan after three cycles of etoposide and carboplatin chemotherapy. The multiple nodules were markedly decreased.
      Figure thumbnail figs2
      Supplemental Figure 2Next-generation sequences (NGS) of the patients in case 1 and case 2. (A) In case 1, NGS showed persistence of the L858R mutation and EGFR gene amplification. In case 2, NGS showed persistence of the exon 19 deletion. (B) In case 1, EGFR gene amplification was noted. (C) There were no abnormalities of retinoblastoma (RB) genes in either case.

      References

        • Sequist L.V.
        • Waltman B.A.
        • Dias-Santagata D.
        • et al.
        Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.
        Sci Transl Med. 2011; 3: 75ra26
        • Oser M.G.
        • Niederst M.J.
        • Sequist L.V.
        • et al.
        Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin.
        Lancet Oncol. 2015; 16: e165-e172
        • Cross D.A.
        • Ashton S.E.
        • Ghiorghiu S.
        • et al.
        AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.
        Cancer Discov. 2014; 4: 1046-1061
        • Janne P.A.
        • Yang J.C.
        • Kim D.W.
        • et al.
        AZD9291 in EGFR inhibitor–resistant non–small-cell lung cancer.
        N Engl J Med. 2015; 372: 1689-1699
        • Piotrowska Z.
        • Niederst M.J.
        • Karlovich C.A.
        • et al.
        Heterogeneity underlies the emergence of EGFRT790 wild-type clones following treatment of T790M-positive cancers with a third-generation EGFR inhibitor.
        Cancer Discov. 2015; 5: 713-722
        • Thress K.S.
        • Paweletz C.P.
        • Felip E.
        • et al.
        Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M.
        Nat Med. 2015; 21: 560-562