ALK positive lung cancer

Medical condition

ALK positive lung cancer

Micrograph showing ALK positive lung adenocarcinoma. H&E stain.
Specialty| Oncology

ALK positive lung cancer is a primary malignant lung tumor whose cells contain a characteristic abnormal configuration of DNA wherein, most frequently, the echinoderm microtubule-associated protein-like 4 (EML4) gene is fused to the anaplastic lymphoma kinase (ALK) gene. Less frequently, there will be novel translocation partners for the ALK gene, in place of EML4.[1] This abnormal gene fusion leads to the production of a protein that appears, in many cases, to promote and maintain the malignant behavior of the cancer cells.[2]

The transforming EML4-ALK fusion gene was first reported in non-small cell lung carcinoma (NSCLC) in 2007.[3]

## Signs and symptoms[edit]

The signs and symptoms of this cancer include

* A cough that doesn't go away
* Chest pain that gets worse with deep breathing, coughing, or laughing
* Hoarseness
* Weight loss without trying or loss of appetite
* Coughing up blood
* Shortness of breath
* A weak or tired feeling
* Wheezing[4]

## Diagnosis[edit]

### Classification[edit]

Most lung carcinomas containing the ALK gene fusion are adenocarcinomas.

Some studies suggest that the papillary adenocarcinoma and the signet ring cell adenocarcinoma[5] variants are more likely to carry this fused gene than other histological variants.

The median age at diagnosis is around 50 years and the majority are female. [4][6]

## Screening[edit]

Micrograph showing an ALK positive adenocarcinoma of the lung. ALK immunostain.

Screening for ALK positive lung cancer is now a standard of care in the United States and Canada. Screening can be done with immunostaining, FISH, or next-generation sequencing (NGS).[citation needed]

## Treatment[edit]

Crizotinib is a targeted therapy (FDA approved in 2011), manufactured by Pfizer and marketed under the brand name Xalkori and Crizalk that targets the EML4/ALK fusion gene.[citation needed]

Ceritinib is a second generation targeted therapy (FDA approved in 2014), manufactured by Novartis and sold under the brand name Zykadia that also targets the EML4 fusion gene, but as a second generation drug it has a smaller molecule that allows superior penetration of the Blood Brain Barrier (BBB) over Crizotinib and is more capable of protecting the Central Nervous System (CNS).[citation needed]

Alectinib another second generation targeted therapy and was approved (for this) by Japan in 2014[7] and by US FDA in 2015.,[8] manufactured by Genentech and marketed under the brand name Alecensa.

Brigatinib a second generation targeted therapy (FDA approved in 2017), manufactured by Takeda and is marketed under the brand name Alunbrig.

Ensartinib is a second generation targeted therapy (trial drug X-396), manufactured by XCovery.[9]

Lorlatinib is a third generation targeted therapy (FDA approved in 2018), manufactured by Pfizer.[10]

NVL-655 is a fourth generation targeted therapy (currently in clinical trials), developed by Nuvalent.[10][11]

Although treatment with immune checkpoint inhibitors has proved effective with some types of non-small cell lung cancer, it seems to be generally ineffective with ALK positive non-small cell lung cancer.[12]

## Prognosis[edit]

Treatment with crizotinib achieves 60% response rate.[13] However, crizotinib showed no improvement on overall survival compared to chemotherapy.[14] This may be due to the fact that there was a 70% crossover rate to crizotinib in patients treated initially with chemotherapy.[15] Also, patients who tested negative for EML4/ALK fusion had a response rate to crizotinib of up to 35%.[16]

According to patient advocacy group ALK Positive, a study in December 2018 found that the median survival for people with stage 4 (IV) ALK-positive lung cancer was 6.8 years with the right care.[4]

## Epidemiology[edit]

EML4-ALK gene fusions occur almost exclusively in carcinomas arising in non-smokers.[17][18] About 4% of non-small-cell lung carcinomas involve an EML4-ALK tyrosine kinase fusion gene.[19] 4-6% of lung adenocarcinomas involve the fusion gene.[13]

EML4-ALK mutation rarely occurs in combination with K-RAS or EGFR mutations.

## References[edit]

1. ^ Iyevleva, Aglaya G.; Raskin, Grigory A.; Tiurin, Vladislav I.; Sokolenko, Anna P.; Mitiushkina, Natalia V.; Aleksakhina, Svetlana N.; Gariullina, Aigul R.; Strelkova, Tatiana N.; Merkulov, Valery O.; Ivantsov, Alexandr O.; Kuligina, Ekatherina Sh.; Pozharisski, Kazimir M.; Togo, Alexandr V.; Imyanitov, Evgeny N. (28 June 2015). "Novel ALK fusion partners in lung cancer". Cancer Letters. 362 (1): 116–121 - via Science Direct.
2. ^ Soda M, Choi YL, Enomoto M, et al. (August 2007). "Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer". Nature. 448 (7153): 561–6. Bibcode:2007Natur.448..561S. doi:10.1038/nature05945. PMID 17625570. S2CID 2172543.
3. ^ Sasaki T, Rodig SJ, Chirieac LR, Jänne PA (July 2010). "The biology and treatment of EML4-ALK non-small cell lung cancer". Eur. J. Cancer. 46 (10): 1773–80. doi:10.1016/j.ejca.2010.04.002. PMC 2888755. PMID 20418096.
4. ^ a b c ALK Positive (5 February 2023). "What is ALK-Positive lung cancer?". ALK Positive. Archived from the original on 7 October 2020. Retrieved 5 February 2023.
5. ^ Koh Y, Kim DW, Kim TM, et al. (May 2011). "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. 6 (5): 905–12. doi:10.1097/JTO.0b013e3182111461. PMID 21358343. S2CID 38377715.
6. ^ ALK Positive UK (5 February 2023). "Facts". ALK Positive UK. Archived from the original on 17 January 2023. Retrieved 5 February 2023.
7. ^ Japan becomes first country to approve Roche’s alectinib for people with a specific form of advanced lung cancer
8. ^ New Oral Therapy To Treat ALK-Positive Lung Cancer. Dec 2015
9. ^ Xcovery (5 February 2023). "Ensartinib". Xcovery. Archived from the original on 3 December 2022. Retrieved 5 February 2023.
10. ^ a b Ou, Sai-Hong Ignatius; Nagasaka, Misako; Brazel, Danielle; Hou, Yujie; Zhu, Viola W. (November 2021). "Will the clinical development of 4th-generation "double mutant active" ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC?". Translational Oncology. 14 (11): 1–9. doi:10.1016/j.tranon.2021.101191 - via Elsevier.
11. ^ Nuvalent Pipeline (5 February 2023). "Nuvalent Pipeline". Nuvalent. Archived from the original on 8 December 2022. Retrieved 5 February 2023.
12. ^ Jahanzeb, Mohammad; Lin, Huamao M; Pan, Xiaoyun; Yin, Yu; Baumann, Pia; Langer, Corey J (17 September 2020). "Immunotherapy Treatment Patterns and Outcomes Among ALK-Positive Patients With Non-Small-Cell Lung Cancer". Clinical Lung Cancer. 22 (1): 49–57.
13. ^ a b Bayliss, R; Choi, J (March 2016). "Molecular mechanisms that underpin EML4-ALK driven cancers and their response to targeted drugs". Cellular and Molecular Life Sciences. 73 (6): 1209–1224. doi:10.1007/s00018-015-2117-6. PMC 4761370. PMID 26755435.
14. ^ Highlights of prescribing information FDA
15. ^ Solomon, Benjamin J.; Mok, Tony; Kim, Dong-Wan; Wu, Yi-Long; Nakagawa, Kazuhiko; Mekhail, Tarek; Felip, Enriqueta; Cappuzzo, Federico; Paolini, Jolanda; Usari, Tiziana; Iyer, Shrividya; Reisman, Arlene; Wilner, Keith D.; Tursi, Jennifer; Blackhall, Fiona; PROFILE 1014 Investigators (2014). "First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer". New England Journal of Medicine. 371 (23): 2167–2177. doi:10.1056/NEJMoa1408440. hdl:2434/426878. PMID 25470694.
16. ^ Summary of safety and effectiveness data FDA
17. ^ Shaw AT, Yeap BY, Mino-Kenudson M, et al. (September 2009). "Clinical Features and Outcome of Patients With Non–Small-Cell Lung Cancer Who Harbor EML4-ALK". Journal of Clinical Oncology. 27 (26): 4247–4253. doi:10.1200/JCO.2009.22.6993. PMC 2744268. PMID 19667264.
18. ^ Martelli MP, Sozzi G, Hernandez L, et al. (February 2009). "EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues". Am. J. Pathol. 174 (2): 661–70. doi:10.2353/ajpath.2009.080755. PMC 2630573. PMID 19147828.
19. ^ Kumar, V; Abbas AK; Aster JC (2013). "Chapter 5". Robbins Basic Pathology (9th ed.). Elsevier Saunders. p. 212\. ISBN 978-1-4377-1781-5.

## External links[edit]

* Entrez Gene EML4 echinoderm microtubule associated protein like 4 Homo sapiens