Small Cell Lung Cancer in Light/Never Smokers – A Role for Molecular Testing?

Background

Lung cancer is the most common and lethal malignancy in the world.¹ Approximately 85% of cases have histology of non–small cell lung (NSCLC), which includes lung adenocarcinoma (LA), squamous cell carcinoma, and large-cell carcinoma, and the remaining 15% are small cell lung cancer (SCLC). Treatment strategies are directed toward the underlying tumor histology and rely on the assumption that the cancer is primarily one subtype. Within NSCLC, immune checkpoint inhibitors and targeted therapy to driver mutations in EGFR and ALK have revolutionized management with the prolongation of profession-free and overall survivals. Additional targeted therapies include agents targeting MET, RET, ROS1, KRAS, BRAF, and ERBB2 pathways, among an ever-evolving field.² Management of lung cancer with a combined histology or a transformed phenotype is difficult in light of less reported literature.³

This report describes the management of SCLC transformation in a patient with untreated ALK-mutated advanced disease, and a separate case of a de novo SCLC found to have a potentially targetable ERBB2 alteration.

Case Presentations

Case 1

A 71-year-old female presented to the hospital with a 2-month history of nonproductive cough, shortness of breath, and fatigue. Initial assessment revealed decreased breath sounds in the left upper lobe (LUL) region and no palpable lymphadenopathy. Chest CT revealed a large necrotic LUL mass extending to the hilus and aortic arch with mediastinal and pleural invasion (Figure 1). Further staging identified metastases in the brain, liver, and bone, and a clinical stage of T4N3M1c, stage IVB. The patient had a history of early-stage invasive breast cancer treated with a lumpectomy and radiation in 2006, and results of her last mammogram in September 2020 were normal. Her maternal grandmother had unknown cancer, and her mother had cervical cancer. The patient is functionally active, retired, and a previous smoker who quit >46 years ago with a <2 pack-year smoking history.

CT scan of the chest demonstrating a left upper lobe mass, axial view.

Citation: Journal of the National Comprehensive Cancer Network 21, 4; 10.6004/jnccn.2022.7089

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CT scan of the chest demonstrating a left upper lobe mass, axial view.

Citation: Journal of the National Comprehensive Cancer Network 21, 4; 10.6004/jnccn.2022.7089

CT scan of the chest demonstrating a left upper lobe mass, axial view.

Citation: Journal of the National Comprehensive Cancer Network 21, 4; 10.6004/jnccn.2022.7089

The patient completed an endobronchial ultrasound bronchoscopy with biopsies; however, before pathology was reported, she presented to the emergency department for severe hip pain and was diagnosed with an acute pathologic fracture of her left inferior public rami. While admitted, the patient completed a liver biopsy that demonstrated SCLC with immunohistochemistry (IHC) expression for pan-keratin, chromogranin, synaptophysin, and TTF1, along with rare p40 staining and a Ki-67 >90%. Based on her minimal smoking history, molecular testing was performed, which identified an ALK translocation mutation by fluorescence in situ hybridization and next-generation sequencing, as well as a TP53 mutation (C.578A>T, p.His193Leu) (Figure 2A–E). The patient received her first cycle of carboplatin/etoposide as an inpatient, which improved her symptoms and paraneoplastic syndrome of inappropriate antidiuretic hormone secretion.

Case 1: (A) ALK, (B) chromogranin, (C) KI-67, (D) hematoxylin-phloxine-saffron, and (E) synaptophysin immunohistochemical expression from a metastatic liver lesion biopsy (original magnification ×20).

Citation: Journal of the National Comprehensive Cancer Network 21, 4; 10.6004/jnccn.2022.7089

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Case 1: (A) ALK, (B) chromogranin, (C) KI-67, (D) hematoxylin-phloxine-saffron, and (E) synaptophysin immunohistochemical expression from a metastatic liver lesion biopsy (original magnification ×20).

Citation: Journal of the National Comprehensive Cancer Network 21, 4; 10.6004/jnccn.2022.7089

Case 1: (A) ALK, (B) chromogranin, (C) KI-67, (D) hematoxylin-phloxine-saffron, and (E) synaptophysin immunohistochemical expression from a metastatic liver lesion biopsy (original magnification ×20).

Citation: Journal of the National Comprehensive Cancer Network 21, 4; 10.6004/jnccn.2022.7089

The patient completed 4 cycles of chemotherapy with a very good radiographic response of intracranial and hepatic metastases but developed some leptomeningeal disease and thoracic progression of disease <2 months after chemotherapy. She was started on alectinib because of her ALK-mutant molecular profile and its central nervous system penetrance. After 6 months of therapy, she continues to tolerate treatment and experience a good response in her lung mass and leptomeningeal disease (Figure 3A) and stable hepatic metastases (Figure 3B), with an acceptable grade 2 increased bilirubin toxicity.

Case 1: (A) CT scan of the chest demonstrating a response in the left upper lobe mass while on alectinib (arrow), axial view; (B) CT scan of the abdomen demonstrating stable hepatic metastases while on alectinib (arrow), axial view.

Citation: Journal of the National Comprehensive Cancer Network 21, 4; 10.6004/jnccn.2022.7089

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Case 1: (A) CT scan of the chest demonstrating a response in the left upper lobe mass while on alectinib (arrow), axial view; (B) CT scan of the abdomen demonstrating stable hepatic metastases while on alectinib (arrow), axial view.

Citation: Journal of the National Comprehensive Cancer Network 21, 4; 10.6004/jnccn.2022.7089

Case 1: (A) CT scan of the chest demonstrating a response in the left upper lobe mass while on alectinib (arrow), axial view; (B) CT scan of the abdomen demonstrating stable hepatic metastases while on alectinib (arrow), axial view.

Citation: Journal of the National Comprehensive Cancer Network 21, 4; 10.6004/jnccn.2022.7089

Case 2

A 78-year-old, lifelong nonsmoking female presented with extensive pulmonary, osseous, and hepatic metastases with a liver biopsy consistent with SCLC (Figure 4). Due to her nonsmoking status, next-generation testing was ordered, which revealed an ERBB2 exon 20 insertion mutation, as well as TP53 and RB1 mutation. She received several rounds of platinum/etoposide chemotherapy, as well as durvalumab and radiation therapy. She did not receive any ERBB2-targeted therapy.

Case 2: hematoxylin-phloxine-saffron immunohistochemical expression from a metastatic liver lesion biopsy (original magnification ×20).

Citation: Journal of the National Comprehensive Cancer Network 21, 4; 10.6004/jnccn.2022.7089

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Case 2: hematoxylin-phloxine-saffron immunohistochemical expression from a metastatic liver lesion biopsy (original magnification ×20).

Citation: Journal of the National Comprehensive Cancer Network 21, 4; 10.6004/jnccn.2022.7089

Case 2: hematoxylin-phloxine-saffron immunohistochemical expression from a metastatic liver lesion biopsy (original magnification ×20).

Citation: Journal of the National Comprehensive Cancer Network 21, 4; 10.6004/jnccn.2022.7089

Discussion

SCLC in light/never smokers is very rare and comprises approximately <2.5% of cases.^4,5 These patients are more likely to be female, to be within the age groups of 35 to 49 years or ≥80 years, and to present at an extensive stage.⁵ Risk factors for SCLC in light/never smokers are not well understood, but second-hand environmental tobacco smoke, occupational exposures (asbestos, chromium, arsenic), and radon are thought to be contributing factors.⁶ The genomic profile of light/never smokers with SCLC was characterized by lower tumor mutational burden, a lower frequency of TP53 mutations, and a higher frequency of EGFR, MET, and SMAD4 mutations.^5,7 In a large retrospective multicenter cohort study of patients with SCLC, there were no overall survival differences between light/never smokers and smokers, and each had a poor prognosis.⁵

The histologic transformation of SCLC from NSCLC is becoming more frequent, with an incidence of up to 15%.^3,8 The most common mechanism is acquired resistance to chemotherapy and radiation, but this mechanism now includes acquired resistance to targeted therapies with tyrosine kinase inhibitors (TKIs).³ Through sequential biopsies, several studies have illustrated SCLC transformation in both EGFR- and ALK-mutant LAs based on histology and positive IHC staining for synaptophysin, chromogranin, or neural cell adhesion molecule.³ The loss of sensitivity to TKIs following SCLC transformation appears to be mediated by the downregulation and expression of EGFR or ALK proteins, although target-dependent and target-independent mechanisms of resistance may also play a role. For example, within EGFR-mutated LA, an exon 20 (Thr790Met) target mutation or MET gene amplification with an increase in non-EGFR signaling pathways could be contributing factors.^3,8

However, in studies by Norkowski et al⁹ and Lee et al,¹⁰ SCLC transformation occurred in patients with untreated EGFR- and ALK-mutated LA, establishing that transformation is not exclusively the result of targeted inhibition.³ These studies promote the idea that transformation could be predisposed at an early stage by genetic factors.^3,8 Both preclinical and clinical studies have shown that RB1 inactivation is essential for SCLC development but alone not sufficient.^3,8 Therefore, additional pathways such as NOTCH-achaete-scute homolog 1 and TP53 could also have essential roles.⁸ Like classic SCLC, Niederst et al¹¹ observed that tumors with SCLC transformation had a loss of tumor suppression via RB1 and TP53 inactivation, a reduced or absent EGFR protein expression, an increased sensitivity to BCL-2 inhibition, and epigenetic changes.⁸ In a study by Lee et al,¹⁰ patients with EGFR-mutant LA and inactivation of RB1 and TP53 have a 43-fold increased risk of transformation to SCLC. However, a similar study by Offin et al¹² found that not all patients with all 3 mutations undergo SCLC transformation, thus reiterating the importance of additional pathways and epigenetic changes.⁸

An additional proposed transformation mechanism could be shared progenitor cells. Although alveolar type II (AT2) cells are established progenitor cells of LA, murine models have demonstrated the development of SCLC from AT2 cells with the targeted disruption of RB1 and TP53.³ Further, the presence of the EGFR mutation and activation of EGFR signaling drives the proliferation and differentiation of AT2 cells.³ Therefore, when additional genetic events occur (eg, RB1 inactivation), the AT2 cells could subsequently transform to SCLC and become independent of EGFR signaling.³

There is no consensus on the definition of SCLC transformation from NSCLC, its differences from primary SCLC, and a lack of clinical trials exploring management. In a study by Ferrer et al,¹³ the median time to SCLC transformation was shorter in patients with EGFR mutations than in those without mutations (16 vs 26 months; P=.01) and there was no significant difference in survival after transformation (9 vs 10 months) depending on EGFR mutation status. Patients with SCLC transformation tend to have a poor prognosis.⁸ Use of platinum/etoposide cytotoxic chemotherapy yields similar responses between mutant and wild-type groups, with response rates between 40% and 45%.¹³ Other potential therapeutics include BCL-2 inhibitors to target apoptosis resistance, EZH2 inhibitors to modulate epigenetics pathways, or CHK1, PLK1, and AURKA inhibitors for synthetic lethality from RB1 inactivation.⁸

Our case is unique because SCLC transformation occurred before the initiation of an ALK TKI, there is no RB1 mutation, and the patient continues to experience a clinical response on targeted therapy after experiencing disease progression on standard cytotoxic therapy. However, her continued clinical response and outcome are unknown. The second case is indicative of the same phenomenon in an ERBB2-altered lung cancer.

Conclusions

Molecular testing in SCLC to identify driver mutations in patients with light/never smoking histories should be considered in order to help understand the incidence and ultimate optimal management strategies. In our patient, chemotherapy followed by a targeted inhibitor was chosen due to the presence of the ALK rearrangement, as well as a somewhat discordant response to induction chemotherapy, suggesting possible progression of the ALKinhibitor–sensitive component.