A new research paper on small cell lung cancer co-authored by NSW Health Pathology cytologist Shailendra Gune points to more personalised treatment options for patients with this aggressive form of cancer, using routine diagnostic biopsy samples.

Small cell lung can­cer (SCLC) is one of the most aggres­sive and hard to treat forms of cancer.

It grows quick­ly, spreads ear­ly, and is often diag­nosed when surgery is no longer possible.

Sur­vival rates remain low and for many years there have been lim­it­ed treat­ment options.

Now, new research co-authored by Shailen­dra Gune, head of Cytol­ogy at NSW Health Pathology’s Liv­er­pool Lab­o­ra­to­ry, is help­ing to change that picture.

By analysing rou­tine diag­nos­tic biop­sy sam­ples using advanced mol­e­c­u­lar tech­niques, the study pro­vides new insights into why SCLC behaves dif­fer­ent­ly from patient to patient and how treat­ments could be bet­ter matched to each individual.

Making the most of routine diagnostic samples

Unlike many oth­er can­cers, SCLC is rarely removed sur­gi­cal­ly. Instead, diag­no­sis is usu­al­ly made using small biop­sy sam­ples col­lect­ed dur­ing a pro­ce­dure called Endo Bronchial Ultrasound–guided Trans Bronchial Nee­dle Aspiration.

These sam­ples are essen­tial for diag­no­sis but have tra­di­tion­al­ly been seen as too small for large scale mol­e­c­u­lar analysis.

In this study, researchers showed that these rou­tine­ly col­lect­ed sam­ples can be used for cut­ting edge mul­ti-omics research.

Tumour sam­ples from 82 patients were analysed using DNA methy­la­tion pro­fil­ing, whole genome sequenc­ing, RNA sequenc­ing, and blood based (cell free DNA) testing.

“This work shows that diag­nos­tic sam­ples already being col­lect­ed in hos­pi­tals can also unlock very pow­er­ful mol­e­c­u­lar infor­ma­tion,” said Shailendra.“That opens the door to research find­ings that are much clos­er to real world patient care.”

Identifying four distinct types of small cell lung cancer

Using DNA methy­la­tion analy­sis, a way of read­ing chem­i­cal changes that reg­u­late how genes are switched on and off, the research team iden­ti­fied four dis­tinct mol­e­c­u­lar groups of SCLC.

These groups dif­fered not only in their biol­o­gy, but also in patient sur­vival and poten­tial treat­ment opportunities.

• Group 1 – Immune Enriched Tumours
  These can­cers showed signs of immune activ­i­ty, includ­ing high­er lev­els of immune cells called CD8+ T cells. Patients in this group tend­ed to live longer, sug­gest­ing their tumours may be more respon­sive to cer­tain therapies.
• Group 2 – ASCL1-dri­ven tumours
  This was the largest group. These can­cers showed high lev­els of spe­cif­ic genes, includ­ing SLFN11 and DLL3, which are already being explored as drug tar­gets. This group may ben­e­fit most from emerg­ing tar­get­ed treatments.
• Group 3 – NEU­ROD1-dri­ven tumours
  These tumours showed dif­fer­ent gene activ­i­ty and a greater pres­ence of sup­port­ive tis­sue cells called fibrob­lasts, sug­gest­ing anoth­er dis­tinct bio­log­i­cal path­way dri­ving disease.
• Group 4 – Non-Neu­roen­docrine tumours
  This group had the poor­est sur­vival out­comes. How­ev­er, it also showed high expres­sion of TACSTD2, point­ing to a pos­si­ble new ther­a­peu­tic tar­get for these patients.

Across most tumour groups, the gene SEZ6 was also high­ly active, high­light­ing anoth­er poten­tial tar­get for future therapies.

Why tumour differences matter

At present, most peo­ple with SCLC receive sim­i­lar treat­ments, usu­al­ly a com­bi­na­tion of chemother­a­py and immunother­a­py. While this approach has helped some patients, only about one in five see last­ing benefit.

This research shows that SCLC is not a sin­gle dis­ease, but actu­al­ly four dis­tinct types, each with its own bio­log­i­cal fin­ger­print. Under­stand­ing these dif­fer­ences is critical.

“Treat­ments that work well for one mol­e­c­u­lar group may be far less effec­tive for anoth­er,” said Shailendra.

“By recog­nis­ing this diver­si­ty, we can start to think about more per­son­alised treat­ment strate­gies rather than a one-size-fits-all approach.

“Our 2024 study (Eval­u­a­tion of Endo­bronchial Ultra­sound-Guid­ed Trans­bronchial Nee­dle Aspi­ra­tion (EBUS-TBNA) Sam­ples from Advanced Non-Small Cell Lung Can­cer for Whole Genome, Whole Exome and Com­pre­hen­sive Pan­el Sequenc­ing – DOI: 10.3390/cancers16040785) showed that rou­tine diag­nos­tic sam­ples were strong enough for advanced genet­ic testing.

“This new work takes that a step fur­ther by using those sam­ples to define these can­cer sub­groups and high­light new pos­si­bil­i­ties for tar­get­ed therapy.”

Bridging research and clinical care

The study demon­strates that DNA methy­la­tion test­ing on stan­dard diag­nos­tic sam­ples can cap­ture both the inter­nal fea­tures of the tumour and its sur­round­ing envi­ron­ment, includ­ing immune cells. This makes methy­la­tion pro­fil­ing a pow­er­ful tool for future clin­i­cal decision-making.

The find­ings also help bridge a long-stand­ing gap in SCLC research. Because tumour tis­sue is so lim­it­ed, SCLC has his­tor­i­cal­ly been under­rep­re­sent­ed in major can­cer genomics projects.

This work shows that it is pos­si­ble to over­come those bar­ri­ers using sam­ples already col­lect­ed in rou­tine care.

While fur­ther research and clin­i­cal tri­als are need­ed, this study lays impor­tant ground­work for pre­ci­sion oncol­o­gy in small cell lung can­cer, where treat­ment is guid­ed by the mol­e­c­u­lar fea­tures of each patient’s tumour.

“Our goal is bet­ter out­comes for patients,” said Shailendra.

“By under­stand­ing the biol­o­gy of these can­cers in more detail, we can help guide future treat­ments and improve care.

“This research high­lights the crit­i­cal role NSW Health Pathol­o­gy plays in trans­lat­ing lab­o­ra­to­ry sci­ence into mean­ing­ful clin­i­cal impact, using every­day diag­nos­tic work to dri­ve inno­va­tion and improve patient outcomes.”

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