What cancer is most likely to mutate to small cell lung cancer (SCLC)?

From the Guidelines

Non-small cell lung cancer (NSCLC) is most likely to mutate to small cell lung cancer (SCLC). This transformation typically occurs in patients with NSCLC who have undergone treatment with targeted therapies, particularly EGFR tyrosine kinase inhibitors (TKIs) like osimertinib, erlotinib, or gefitinib, as reported in a study published in the Journal of Clinical Oncology 1. The transformation represents a resistance mechanism that develops in approximately 3-14% of EGFR-mutated NSCLC cases treated with these medications.

Key Points

• The histological transformation is believed to occur through complex genetic mechanisms, including the loss of RB1 and TP53 tumor suppressor genes, which are characteristic genetic alterations in SCLC.
• Patients with NSCLC who experience rapid disease progression, especially with new, aggressive metastatic patterns or dramatically elevated neuroendocrine markers despite ongoing targeted therapy, should be evaluated for potential SCLC transformation.
• A repeat biopsy of progressing lesions is typically required to confirm the histological change and guide appropriate treatment modifications, usually switching to standard SCLC chemotherapy regimens like platinum/etoposide combinations, as suggested by a study published in the Annals of Oncology 1.

Treatment Considerations

• The use of EGFR inhibitors may be continued with chemotherapy in patients with NSCLC harboring an EGFR mutation that has transformed to SCLC, although the evidence quality is low and the strength of recommendation is weak 1.
• Immunotherapy is not recommended in this setting due to insufficient evidence, and clinical trial enrollment should be offered whenever possible 1.
• The frequency of small cell transformation in ROS1 and ALK fusion-positive lung cancers appears relatively low, at 2% and 0.8%, respectively 1.

From the Research

Small Cell Lung Cancer (SCLC) Overview

• Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy with rapid proliferation, early spread, and poor survival 2.
• It accounts for 14% of lung cancer cases and is characterized by early dissemination and a rapid, aggressive clinical course 3.

Mutation and Progression

• The probable initiating molecular events in SCLC are inactivation of TP53 and RB1, as well as frequent disruption of several signalling networks, including Notch signalling 4.
• SCLC tumors invariably develop resistance to multiple chemotherapeutic agents, making treatment challenging 3.

Cancer Types that May Mutate to SCLC

• There is no clear evidence to suggest that a specific type of cancer is most likely to mutate to SCLC.
• However, it is known that SCLC can arise from neuroendocrine cells in the lung, and that it may share some molecular characteristics with other neuroendocrine tumors 4.

Treatment and Management

• Treatment for SCLC typically involves a combination of chemotherapy and immunotherapy, with platinum-etoposide being a common regimen 2, 5.
• For patients with platinum-sensitive SCLC, retreatment with platinum and etoposide may be a preferred option 5.
• Participation in clinical trials is also recommended, as new therapies and combination regimens are being developed to improve treatment outcomes for SCLC patients 5.