Background of the need for targeted therapy options and platinum-based therapy responses in EGFR and ALK-mutated lung adenocarcinoma

Year 2023, Volume: 14 Issue: 3, 645 - 650, 30.09.2023

Abdülkadir Erçalışkan , Zeynep Turna

https://doi.org/10.18663/tjcl.1346853

Abstract

Aim: To present our experience in EGFR and EML-4/ALK-mutated lung adenocarcinoma patients.
Material and Methods: 2580 patients were retrospectively evaluated. Only stage-4 lung adenocarcinoma patients who treated with at least 2-cycles of platinum-based regimens at frontline were included.
Results: Among 105 eligible patients, EGFR and EML-4/ALK mutations was detected in 14 and 4 patients. 75 were wild- type for both mutations. The median age and age of diagnose was 61 and 58.5, respectively. 81% was male and 78% was smoker. EGFR and EML-4/ALK-mutant patients were predominantly female and non-smoker (EGFR; p=0.025 and 0.002, EML-4/ALK; p=0.003 and 0.012,respectively). EML-4/ALK- mutant patients were significantly younger than EML- 4/ALK wild-type (p=0.02) (Table 1). EGFR exon-19, 20 and 21 mutations were associated with liver, bone and pleural metastases, respectively (p=0.046, 0.05 and 0.035,respectively). After firstline platinum-based chemotherapy, complete remission (CR) and partial remission (PR) rates were 4.7% and 24.6%,respectively. Concurrent radiotherapy and absence of bone metastases at diagnosis were significant factors influencing firstline platinum-based therapy responses (p=0.004 and p=0.046,respectively). EGFR or EML-4/ALK mutation status didn’t show significant difference in terms of platinum- based treatment response (p=0.933 and 0.184,respectively). Median progression-free survival (PFS) was 10 months. The observed effect of concurrent radiotherapy and the presence of bone metastases on treatment response didn’t reflected in the PFS results (p=0.079 and 0.285,respectively).
Conclusion: The presence of EGFR and ALK mutations does not effect the treatment response of platinum-based regimens. The association of EGFR exon subsets with metastasis points is worth investigating.

Keywords

EGFR, EML-4/ALK, ALK, platinum, lung adenocarcinoma

EGFR ve ALK mutasyonu taşiyan akciğer adenokarsinomlarinda platin bazli tedavi yanitlari ve hedefe yönelik tedavi ihtiyacinin arka plani

Abstract

Amaç: EGFR ve EML-4/ALK mutasyonlu akciğer adenokarsinomu hastalarındaki deneyimlerimizi sunmak.
Gereç ve Yöntemler: 2580 hasta retrospektif olarak değerlendirildi. Çalışmaya yalnızca evre 4 akciğer adenokarsinomu olup ilk sıra en az 2 siklus platin bazlı rejimlerle tedavi edilen hastalar dahil edilmiştir.
Bulgular: Çalışmaya uygun 105 vakanın 14’ü EGFR, 4’ü EML-4/ALK mutant iken 75 vaka her iki mutasyonu da taşımıyordu. Medyan yaş ve tanı yaşı sırasıyla 61 ve 58.5 idi. %81'i erkekti ve %78'i sigara içiyordu. EGFR ve EML-4/ALK-mutant hastalar ağırlıklı olarak kadındı ve sigara içmiyordu (sırasıyla EGFR; p=0.025 ve 0.002, EML-4/ALK; p=0.003 ve 0.012). EML-4/ALK- mutant hastalar, bu mutasyonu taşımayanlara göre daha gençti (p=0,02) (Tablo 1). EGFR ekson-19, 20 ve 21 mutasyonları sırasıyla karaciğer, kemik ve plevral metastazlarla ilişkiliydi (sırasıyla p=0.046,
0.05 ve 0.035). Birinci basamak platin bazlı kemoterapiden sonra tam remisyon ve kısmi yanıt oranları sırasıyla %4,7 ve %24,6 idi. Eşzamanlı radyoterapi ve tanı sırasında kemik metastazlarının olmaması birinci basamak platin bazlı tedavi yanıtlarını etkileyen faktörlerdi (sırasıyla p=0.004 ve p=0.046). EGFR veya EML-4/ALK mutasyon durumu platin bazlı tedavi yanıtı açısından anlamlı fark göstermemiştir (sırasıyla p=0,933 ve 0,184). Medyan progresyonsuz sağkalım 10 ay iken eşzamanlı radyoterapi ve kemik metastazının tedavi yanıtı üzerinde gözlenen etkisi PFS sonuçlarına yansımamıştır (sırasıyla p=0,079 ve 0,285).
Sonuçlar: EGFR ve ALK mutasyonlarının varlığı, platin bazlı rejimlerin tedavi yanıtını etkilememektedir. EGFR ekson alt gruplarının metastaz noktaları ile ilişkisi araştırılması gereken bir nokta olarak saptanmıştır.

Keywords

EGFR, EML-4/ALK, ALK, platin, akciğer adenokarsinomu.

References

• Planchard D, Popat S, Kerr K et al. ESMO Guidelines Committee. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow- up. Ann Oncol. 2018 Oct 1;29(Suppl 4): iv192-iv237. doi: 10.1093/annonc/ mdy275. Erratum in: Ann Oncol. 2019 May;30(5):863-870. PMID: 30285222.
• Cappuzzo F, Ligorio C, Toschi L et al. EGFR and HER2 gene copy number and response to first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). J Thorac Oncol. 2007 May;2(5):423-9. doi: 10.1097/01.JTO.0000268676.79872.9b. Erratum in: J Thorac Oncol. 2007 Jul;2(7):676. Ligorio, Claudio [corrected to Ligorio, Claudia]. PMID: 17473658.
• Ettinger DS, Wood DE, Aisner D L et al. NCCN Guidelines® Insights: Non–Small Cell Lung Cancer, Version 2.2023: Featured Updates to the NCCN Guidelines. J Natl Compr Canc Netw., 21(4), 340-350.
• M i t s u d o m i T, K o s a k a T, Ya t a b e Y. B i o l o g i c a l a n d c l i n i c a l i m p l i c a t i o n s o f EGFR mutations in lung cancer. Int J Clin Oncol. 2006 Jun;11(3):190- 8. doi: 10.1007/s10147- 006-0583-4. PMID: 16850125.
• Schuette W, Schirmacher P, Eberhardt WE et al. EGFR mutation status and first-line treatment in patients with stage III/IV non-small cell lung cancer in Germany: an observational study. Cancer Epidemiol Biomarkers Prev. 2015 Aug;24(8):1254-61. doi: 10.1158/1055-9965. EPI-14-1149. Epub 2015 Jun 12. PMID: 26070531.
• Yang P, Kulig K, Boland JM et al. Worse disease-free survival in never-smokers with ALK+ lung adenocarcinoma. J Thorac Oncol. 2012 Jan;7(1):90-7. doi: 10.1097/JTO.0b013e31823c5c32. PMID: 22134072; PMCID: PMC3931519.
• Shaw AT, Yeap BY, Mino-Kenudson M et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009 Sep 10;27(26):4247-53. doi: 10.1200/JCO.2009.22.6993. Epub 2009 Aug 10. PMID: 19667264; PMCID: PMC2744268.
• Kalikaki A, Koutsopoulos A, Hatzidaki D et al. Clinical outcome of patients with non- small cell lung cancer receiving front- line chemotherapy according to EGFR and K-RAS mutation status. Lung Cancer. 2010 Jul;69(1):110-5. doi: 10.1016/j. lungcan.2009.09.010. Epub 2009 Oct 24. PMID: 19854533.
• Koh Y, Kim DW, Kim TM et al. Clinicopathologic characteristics and outcomes of patients with anaplastic lymphoma kinase- positive advanced pulmonary adenocarcinoma: suggestion for an effective screening strategy for these tumors. J Thorac Oncol. 2011 May;6(5):905-12. doi: 10.1097/JTO.0b013e3182111461. PMID: 21358343.
• Camidge DR, Kim HR, Ahn MJ et al. Brigatinib versus Crizotinib in ALK-Positive Non- Small-Cell Lung Cancer. N Engl J Med. 2018 Nov 22;379(21):2027-2039. doi: 10.1056/NEJMoa1810171. Epub 2018 Sep 25. PMID: 30280657.
• Ramalingam SS, Vansteenkiste J, Planchard D et al.; FLAURA Investigators. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med. 2020 Jan 2;382(1):41-50. doi: 10.1056/NEJMoa1913662. Epub 2019 Nov 21. PMID: 31751012.
• SEER*Stat Databases: November 2022 Submission [cited 2023 Aug 18]. Available from: https://seer.cancer.gov/statfacts/html/lungb.html
• Wu M, Zhao J, Song SW et al. EGFR mutations are associated with prognosis but not with the response to front-line chemotherapy in the Chinese patients with advanced non- small cell lung cancer. Lung cancer. 2010; 67(3), 343-347. PMID: 19477549.
• Dziadziuszko R, Holm B, Skov BG et al. Epidermal growth factor receptor gene copy number and protein level are not associated with outcome of non-small-cell lung cancer patients treated with chemotherapy. Ann Oncol. 2007;18(3), 447-452. PMID: 17082511.
• Hotta K, Kiura K, Toyooka S et al. Clinical significance of epidermal growth factor receptor gene mutations on treatment outcome after first-line cytotoxic chemotherapy in Japanese patients with non-small cell lung cancer. J Thorac Oncol. 2007;2(7), 632-637. PMID: 17607119.