A profile of lung cancer in the young population with a highlight on the Indian perspective

Authors

Ghazal Tansir

Aparna Sharma

Sachin Khurana

Deepam Pushpam

Prabhat Singh Malik

Doi

10.3389/fonc.2025.1614463

PMID: 27346245 · DOI: 10.3389/fonc.2025.1614463 · Journal: Frontiers in Oncology (2025)

TL;DR

Tansir et al. review the literature on young-onset lung cancer (YLC), defined variably across studies but generally as non-small cell lung cancer (NSCLC) in patients under 40–50 years of age. They synthesize epidemiology (1–10% of NSCLC in Asians, ~2% in Caucasians), risk factors (tobacco, secondhand smoke, indoor/outdoor air pollution, germline susceptibility), and the molecular landscape — emphasizing enrichment of targetable EGFR mutations and ALK/ROS1 fusions and depletion of KRAS/BRAF/MET alterations relative to older patients. The review puts particular focus on the Indian setting, where lung cancer presents about a decade earlier than the global median, and highlights gaps in oncofertility care, pregnancy management, and access to ALK-targeted tyrosine kinase inhibitors.

Cohort & data

  • Narrative review article — no primary cohort. Synthesizes ≥40 published studies of young-onset NSCLC and lung adenocarcinoma, spanning Caucasian, Asian, African-American and Indian patient populations.
  • Anchored heavily on a recent Indian YLC cohort by Malik et al. (n=133, age <40 yrs, profiled on the TruSight Oncology 500 panel) and on a cBioPortal for Cancer Genomics re-analysis by Hou et al. (n=177, Asian).
  • Familial-aggregation and germline-susceptibility tables draw on case-control studies (Schwartz 1996, Kreuzer 1998, Hemminki 2005, Cassidy 2008) and on whole-exome (whole-exome-seq), whole-genome (whole-genome-seq) and targeted-NGS (targeted-dna-seq) studies in YLC.

Key findings

  • Prevalence of YLC. <2% of Caucasian and <5% of Chinese NSCLC patients are aged <45 years; 1–10% of newly diagnosed NSCLC are <40 years across Asian series. Indian patients present approximately a decade earlier than the global median age of 70.
  • Smoking is less explanatory in YLC. Only ~30% of Asian YLC patients are current/former smokers and the median exposure duration is ~12 years vs ~49 years in Europeans. In Malik et al.’s Indian YLC cohort, only ~21% used tobacco.
  • Air pollution risk skews young. Relative risk of air-pollution-attributable lung cancer is 1.63 in patients <50 yrs vs 1.11 (50–64) and 1.15 (>65); outdoor air pollution is a Group I carcinogen.
  • Familial aggregation. International Lung Cancer Consortium meta-analysis (≈24,000 cases / 23,000 controls) reports a 1.5-fold increase in lung cancer risk with significant family history. Schwartz et al. (1996) found a 7.2-fold risk in non-smokers aged 40–59 with a first-degree relative with lung cancer.
  • Germline P/LP variants. Wei et al. report odds ratios of 4.1 for BRCA1 and 29.2 for TP53 pathogenic/likely-pathogenic variants in YLC. BRCA2, TP53 and other Fanconi-anemia-pathway genes advanced lung adenocarcinoma onset by 12.2 (95% CI 2.5–20.6), 9.0 (95% CI 0.5–16.5) and 6.1 years respectively in an accelerated-failure-time analysis.
  • Indian familial cohort. Of 78 Indian NSCLC patients with affected first/second-degree relatives, 17% (13/78) carried P/LP germline variants in BRCA1 (n=1), BRCA2 (n=2), CHEK2 (n=1), ATM (n=2), BAP1 (n=1), FANCA (n=1), FANCI (n=1), FANCM (n=1), LZTR1 (n=2) and XRCC3 (n=1).
  • Female enrichment. YLC cohorts show a higher female proportion than older NSCLC (e.g., 48.7% vs 41.9% in SEER, Subramanian 2010; 26% vs 14.5% in Vashistha’s Indian cohort, p significant; 41% female in Malik et al.).
  • Stage distribution. 50–70% of YLC patients present with stage IV disease; Malik et al. report 91.7% stage IV including 64% with multi-site metastasis. Brain metastasis is more frequent in YLC (39% vs 25% during disease course; 18.5% vs 9.5% as initial site).
  • Oncogenic drivers enriched in YLC. Targetable alterations are present in 57–70% of YLC vs ~52% in older patients (Sacher et al., p<0.001). ALK rearrangements, ROS1 fusions and EGFR mutations are over-represented; KRAS, BRAF and MET alterations are under-represented.
  • EGFR mutation pattern. Hsu et al. report 60.6% EGFR mutations in YLC vs 52.5% in older patients (p significant). EGFR exon 19 deletions are more common in young patients while exon 20 insertions are higher in older (8% vs 1%, statistically significant).
  • Fusion enrichment. Yang et al. report 23.3% fusions in young vs 5.9% in older; EML4 is the partner gene in >80% of ALK rearrangements (Tian et al.). cBioPortal re-analysis (Hou et al. 2020) showed 9.5% RET rearrangements in YLC vs 1% in patients >45 years.
  • Indian YLC genomics (Malik et al., 2025). TruSight Oncology 500 profiling of 133 patients found EGFR mutations 35.51% (deletion 19 52.6%, L858R 31.5%, exon 20 insertion 10.5%, compound 5.2%), ALK rearrangement 65.7%, ROS1 rearrangement 7.25%, KRAS mutation 3.7% (G12C 40%, G12D 60% of KRAS-mutant), TP53 co-mutation 1.5%, and an ERC1–RET fusion in 0.75%.
  • Indian driver landscape (Sharma et al.). 80.6% of Indian NSCLC patients harbor driver mutations: TP53 37%, EGFR 34.1%, KRAS 13.3%, ALK 8.8%; ALK (24.4%) and ROS1 (7.5%) fusions are more prevalent in patients <40 years while KRAS (13.6%) is enriched in older patients.
  • Survival outcomes. YLC generally has equal or better OS than older NSCLC across stages: e.g., Thomas et al. report 5-year lung-cancer-specific survival of 9.7% vs 4.2% in metastatic disease (p significant); median OS in Malik et al.’s Indian YLC cohort was 26 months (95% CI 15.56–32.43). The very young (<30 yrs) subset had poorer median OS of 15.67 months (95% CI 5.86–30.03), suggesting worse biology.
  • Immunotherapy benefit favors younger patients. In a cohort of 53,719 patients, 2-year survival improved most in those <55 years post-2011 (37.7% → 50.3%) with broader immunotherapy uptake.

Genes & alterations

  • EGFR — Mutations more prevalent and enriched for exon 19 deletion in YLC (Hsu et al.: 60.6% vs 52.5%; Sugiyama et al.). Drives use of gefitinib and osimertinib.
  • ALK — Rearrangements (most often EML4–ALK in >80% of cases per Tian et al.) over-represented in YLC; targetable with crizotinib and lorlatinib.
  • ROS1 — Fusions present in ~6–7% of YLC (Wu et al., Malik et al.) vs <2% in older NSCLC.
  • RET — Rearrangements 9.5% in YLC vs 1% in patients >45 years per cBioPortal analysis (Hou et al. 2020); ERC1–RET fusion observed in Malik et al.’s Indian cohort.
  • KRAS — Lower frequency in YLC (~9% in <40 vs ~30% in 60–69 years); G12C and G12D dominate in the few YLC KRAS-mutant cases.
  • BRAF, MET — Lower frequency in YLC. MET exon 14 skipping is age-skewed: 0.72% (≤50 yrs), 1.1% (51–69 yrs), 3.25% (>70 yrs); pivotal trials of tepotinib and capmatinib enrolled patients up to 74 years old.
  • ERBB2 (HER2) — Hou et al. reported 13.8% HER2 amplification in YLC vs 4.4% in older patients; conflicting data exists.
  • TP53 — Co-mutated with EGFR more commonly in YLC (Hou et al.); hotspot residues R248, R273, G245, R282 (Vavalà et al.).
  • BRCA1, BRCA2 — Pathogenic germline variants enriched in YLC: BRCA1 OR=4.1, BRCA2 advances onset by 12.2 years; specific exome variants p.Cys47Arg (BRCA1) and p.Arg2784Trp (BRCA2) reported by Donner et al.
  • ATM, CHEK2, BAP1, FANCA, FANCI, FANCM, LZTR1, XRCC3 — Recurrent germline P/LP variants in the Indian familial NSCLC cohort (Rastogi et al.).
  • NTRK1, NTRK2, NTRK3 — Mentioned as rare fusion targets with scarce age-stratified data.

Clinical implications

  • Comprehensive molecular profiling is essential in YLC. Given the 57–70% prevalence of targetable alterations, the authors argue that broad NGS panels (e.g., TruSight Oncology 500) should be standard for young patients to enable personalized therapy.
  • Targeted therapy and immunotherapy work across age strata, but with caveats. Subgroup analyses of trials of EGFR-targeted osimertinib (FLAURA, AURA3) and ALK-targeted lorlatinib/crizotinib (CROWN) showed consistent outcomes by age subgroup. First-line immunotherapy trials (pembrolizumab KEYNOTE-042, KEYNOTE-024) showed comparable survival across an age cut-off of 65; the largest absolute 2-year survival gain post-2011 was in patients <55 years (37.7% → 50.3%).
  • Multimodal aggressive therapy is tolerated. YLC patients have lower comorbidity burden and tolerate full-dose chemo/TKI/multimodal therapy, contributing to better loco-regional outcomes.
  • Access disparities in India. Only 1/63 Indian YLC patients receiving TKIs in Malik et al. received osimertinib (1.5%); 20% of patients with targetable alterations did not receive any TKI. ALK TKIs are not covered by Indian public healthcare schemes whereas low-cost gefitinib is broadly accessible.
  • Oncofertility counseling is mandatory. Patients on TKIs in the curative setting need counseling on gonadal toxicity and washout periods before conception.
  • Pregnancy management. Surgery is feasible across trimesters (preferentially T2). Carboplatin/cisplatin with taxanes (paclitaxel) or vinca alkaloids (vinorelbine) are usable from T2; gemcitabine and pemetrexed remain teratogenic and contraindicated; TKIs and immunotherapy are contraindicated throughout pregnancy.
  • Younger-than-30 subgroup may have worse biology. Median OS of 15.67 months in <30-year-olds (vs 26 months for 30–40-year-olds) suggests this subset deserves dedicated study and possibly intensified surveillance.

Limitations & open questions

  • This is a narrative review without systematic-review methodology; no PRISMA flow, study quality assessment, or quantitative meta-analysis is provided.
  • Definitions of “young” vary widely across cited studies (<35, <40, <45, <50, <55 years), limiting direct comparison and pooling.
  • YLC is grossly under-represented in large-scale genomic resources such as TCGA (only 7% of TCGA-LUAD patients were <40 years; mean age 65.3 in Parry et al.), so estimates of germline-variant prevalence and mutational landscapes are imprecise.
  • The role of ancestry-specific environmental exposures (biomass cooking fuel, indoor air pollution, second-hand smoke, urban PM2.5) in shaping the Indian YLC profile remains under-characterized; gene-environment interaction GWAS in non-Caucasian populations are sparse.
  • Indian-specific data on referral pathways, TKI access, oncofertility services, and psychosocial support are essentially absent; the authors call for multicenter Indian YLC registries.
  • Why the very young (<30 yrs) subset has worse outcomes despite similar driver enrichment is unexplained — possibly reflecting more aggressive biology, delayed diagnosis, or unmeasured germline susceptibility.

Citations from this paper used in the wiki

  • “The most frequent alterations in YLC include EGFR mutations, ALK and ROS1 fusions … alterations such as KRAS and MET mutations are linked to more advanced ages and smoking history” (Section 5).
  • “The analysis from cBioPortal for Cancer Genomics database showed a significantly higher prevalence of RET rearrangements in the YLC group (9.5%) versus those greater than 45 years (1%)” (Section 5.2).
  • “Malik et al. … 133 patients … TruSight Oncology 500 panel on FFPE samples … EGFR mutations (35.51%), ALK rearrangement (65.7%), ROS1 rearrangement (7.25%), KRAS mutation (3.7%), TP53 co-mutation (1.5%), ERC1-RET fusion (0.75%)” (Table 3).
  • “Wei et al. demonstrated the high prevalence of pathogenic/likely pathogenic (P/LP) variants among patients with lung cancer especially in YLC. The odds ratio of 4.1 with BRCA1 and 29.2 with TP53 showed that the P/LP variants of these genes are associated with risk of lung cancer” (Section 3).
  • “BRCA2, TP53 and other Fanconi Anemia genes advanced the age of lung cancer onset by 12.2 (95% CI, 2.5-20.6), 9.0 (95% CI, 0.5-16.5) and 6.1 (-1-12.6) years” (Section 3).
  • “Subset aged less than 30 years: Median OS = 15.67 months (95% CI: 5.86-30.03)” (Table 2, Malik et al. 2025).
  • “Increased use of immunotherapy post-2011 the 2-year survival probability improved maximum in patients aged less than 55 years (37.7% to 50.3%)” (Section 6).
  • “Use of osimertinib in only 1 patient (1.5%) among the 63 of those who received TKIs … 20% of the patients in this study with targetable genomic alterations could not receive TKI” (Section 7.4).

This page was processed by crosslinker on 2026-05-14.