Recurrence as a small cell lung cancer transformation in a resected stage IIIA EGFR-mutated non-small cell lung cancer treated with adjuvant osimertinib: a case report

Introduction

After the results of the ADAURA study showing an improvement in disease free and overall survival in stage II–IIIA resected epithelial growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with osimertinib in comparison to placebo (1), adjuvant therapy with osimertinib has been largely embraced in this population. However, whereas there is increasing data on resistance mechanisms to osimertinib in the metastatic context (2), data on recurrence characteristics in the adjuvant context is still scarce. It has already been shown that the profile of resistance differs between the use of osimertinib in the first line setting compared to its use in further lines (2,3). A particular mechanism of resistance is the histological transformation from adenocarcinoma to small cell lung cancer (SCLC). It occurs in 2% to 15% of patients (4,5) and especially in patients with concurrent EGFR, TP53 and RB1 mutations at baseline (6). We present here the case of a patient treated with adjuvant osimertinib and presenting an SCLC transformation as a recurrence. We present this case in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-830/rc).

Case presentation

A 54-year-old man, never-smoker and with no previous medical history, underwent surgery in May 2020 for a persisting nodular condensation in the right upper lobe, discovered during a severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection. The positron emission tomography (PET) scanner and brain magnetic resonance imaging (MRI) showed no other lesions at baseline. The surgery was a right superior lobectomy with a lymph node resection. The pathologist reported a TTF1⁺ 3.1 cm adenocarcinoma with a papillary and focally micro-papillary architecture and with several other infra-centimetric adenocarcinoma in the same lobe. There were also two foci of in situ adenocarcinoma, infiltration of the visceral pleura, and hilar and peripheral nodal metastasis, hence classifying it as pT3N1M0 [stage IIIA, tumor-node-metastasis (TNM) 8^th edition]. Programmed death-ligand 1 (PD-L1) was not expressed and Rb loss was noted. Next-generation sequencing (NGS) molecular analysis revealed an EGFR exon 19 deletion (p.Glu746_Ala750del) and a TP53 mutation (p.Pro152Alafs*14). Based on these results, the patient received 4 cycles of adjuvant chemotherapy with carboplatin and pemetrexed before starting osimertinib 80 mg daily in August 2020.

In September 2023, 3 years after the initiation of osimertinib, a computed tomography (CT) scan showed the apparition of a 7 cm right pleura-parietal mass with osteolysis of the ninth rib (Figure 1). The PET scanner also showed hypermetabolic pleural micronodules on the same side. The patient underwent biopsy of the pleura-parietal mass, which revealed a small cell carcinoma (TTF1⁺, CD56⁺, synaptophysin⁺, Ki67 95%). NGS analysis on liquid biopsy showed the persistence of the del19 in EGFR (variant allele frequency, 46.9%) and the mutation in TP53 (VAF 39.5%), with amplifications in BCL2L2 and NFKBIA. Osimertinib was pursued and the patient was started on a carboplatin and VP16 regimen with concomitant radiotherapy. He progressed quickly after 4 cycles. He then received 2 cycles of carboplatin, adriamycin and vinblastine and presented with pleural progression. He is now being treated by lurbinectedin.

Figure 1 CT scan of the patient, at the baseline (A) persistent nodular condensation in the right upper lobe, discovered during a SARS-Cov-2 infection in a non-smoker patient (April 2020), and at progression (B) apparition of a 7-cm right pleura-parietal mass with osteolysis of the ninth rib on surveillance CT scan (September 2023). CT, computed tomography; SARS-Cov-2, severe acute respiratory syndrome coronavirus 2.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

The persistence of the EGFR and TP53 mutations, as well as the localization of the recurrence and the non-smoker status suggest a histological transformation of the initial adenocarcinoma into an SCLC, rather than the development of a new cancer.

This case is particularly interesting because in the metastatic context, there is always the possibility that tumor biopsy does not reflect the entirety of the tumor and that the SCLC component might have been present from the start, with selective pressure making it the primary component when treated with osimertinib (7,8). Here, the fact that the entire tumor has been surgically resected, with no SCLC component, suggests that the SCLC recurrence arises from a trans-differentiation of the adenocarcinoma cells. There is one published similar case with a rapid SCLC recurrence in the first 3 months post-surgery while on adjuvant osimertinib, but in this particular case the patient did not undergo lymph node resection, not accounting for the whole initial tumor landscape (9).

The presence of the TP53 mutation and the concomitant Rb loss at baseline, as is the case with our patient, has already been described as associated with SCLC transformation (6,10), and should probably be taken into account while discussing biopsy at recurrence and surveillance protocol. Interestingly, TP53 mutation and Rb loss at baseline seem to be associated with neuroendocrine transformation even without tyrosine kinase inhibitors (TKIs) pressure (11). Whereas we often look for TP53 mutation and it is known to be associated with a poorer prognostic in EGFR NSCLC (12,13), Rb loss is not often evaluated but could be an interesting predictive factor of SCLC transformation (14).

Chemotherapy often yields high response rates in transformed SCLC, however progression free survival and overall survival are short (15,16), as we can see with our patient. In clinical practice, when considering the possibility of SCLC recurrence in patients undergoing osimertinib adjuvant treatment, monitoring should probably be more frequent. Furthermore, in this case, the recurrence occurs in an area where re-biopsy is easy. However, in this setting, in almost half of the cases, re-biopsy is much more difficult (17). When re-biopsy cannot be performed, the possibility of histological transformation into SCLC should be considered if the new treatment appears ineffective.

Conclusions

In conclusion, our case provides evidence of SCLC transformation while on adjuvant osimertinib, in a pT3N1 EGFR, RB1 and TP53-mutated pulmonary adenocarcinoma. This highlights the importance of biopsy on recurrence and the transformation potential of the EGFR, RB1 and TP53-mutated adenocarcinomas.

Acknowledgments

We would like to thank the patient for providing informed consent to the use of his data for this publication.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-830/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-830/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-830/coif). Jean-Bernard Auliac reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Sanofi and Takeda; payment for expert testimony from Janssen, Takeda and Astra Zeneca; and support for attending meetings and/or travel from Astra Zeneca, MSD and BMS. C.C. receives funding support, consulting fees; support for attending meetings and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim, Hoffman-Roche, Takeda, BMS, MSD, Astra Zeneca, Amgen, Janssen and Pfizer. Jean-Baptiste Assié receives funding support, consulting fees and support for attending meetings and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, GSK and Sanofi. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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