TP53 mutations are predictive and prognostic when co-occurring with ALK rearrangements in lung cancer
Authors: D.B. Costa
Journal: Annals of Oncology (2018)

The entity now known as anaplastic lymphoma kinase (ALK) gene rearrangement positive non-small-cell lung cancer (NSCLC) was first identified in 2007 [1.Soda M. Choi Y.L. Enomoto M. et al.Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.Nature. 2007; 448: 561-566Crossref PubMed Scopus (4302) Google Scholar] and the enrollment of patients with these NSCLCs into the original clinical trial of the multitargeted tyrosine kinase inhibitor (TKI) crizotinib dates back to 2008 [2.Kwak E.L. Bang Y.J. Camidge D.R. et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3812) Google Scholar, 3.Camidge D.R. Bang Y.J. Kwak E.L. et al.Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.Lancet Oncol. 2012; 13: 1011-1019Abstract Full Text Full Text PDF PubMed Scopus (1064) Google Scholar, 4.Shaw A.T. Yeap B.Y. 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; 27: 4247-4253Crossref PubMed Scopus (1631) Google Scholar, 5.Shaw A.T. Yeap B.Y. Solomon B.J. et al.Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.Lancet Oncol. 2011; 12: 1004-1012Abstract Full Text Full Text PDF PubMed Scopus (782) Google Scholar]. Fast forward a decade and the preclinical to clinical advances seen in ALK rearranged NSCLC place it at the forefront of the precision oncology revolution that has transformed the palliation of advanced NSCLCs [6.VanderLaan P.A. Rangachari D. Majid A. et al.Tumor biomarker testing in non-small-cell lung cancer: a decade of change.Lung Cancer. 2018; 116: 90-95Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. Four different ALK TKIs—crizotinib (since 2011), ceritinib (since 2014), alectinib (since 2015) and brigatinib (since 2017)—are available worldwide with additional inhibitors, such as lorlatinib, in the last stages of regulatory approval [7.Shaw A.T. Kim D.W. Mehra R. et al.Ceritinib in ALK-rearranged non-small-cell lung cancer.N Engl J Med. 2014; 370: 1189-1197Crossref PubMed Scopus (1044) Google Scholar, 8.Ou S.I. Ahn J.S. De P.L. et al.Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a Phase II Global Study.J Clin Oncol. 2016; 34: 661-668Crossref PubMed Scopus (505) Google Scholar, 9.Kim D.W. Tiseo M. Ahn M.J. et al.Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial.J Clin Oncol. 2017; 35: 2490-2498Crossref PubMed Scopus (439) Google Scholar, 10.Shaw A.T. Felip E. Bauer T.M. et al.Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial.Lancet Oncol. 2017; 18: 1590-1599Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar]. The pace of clinical trial development has been so brisk that evidence-based standards have shifted multiple times and the 'oldest' ALK TKI crizotinib has been displaced in the initial line of treatment by the 'next-generation' ALK TKI alectinib, which is associated with exceedingly high initial overall response rate and median progression-free survival (PFS) times that can almost reach 3 years [11.Peters S. Camidge D.R. Shaw A.T. et al.Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer.N Engl J Med. 2017; 377: 829-838Crossref PubMed Scopus (1463) Google Scholar]. Although biological resistance, mainly through the development of ALK kinase resistant mutations (one example ALK-G1202R), is invariable with ALK TKI monotherapy and the central nervous system a common site of progression; significantly active ALK inhibitors such as lorlatinib can transiently control these resistant clones or brain sanctuary sites, respectively [12.Yoda S. Lin J.J. Lawrence M.S. et al.Sequential ALK inhibitors can select for lorlatinib-resistant compound ALK mutations in ALK-positive lung cancer.Cancer Discov. 2018; 8: 714-729Crossref PubMed Scopus (183) Google Scholar, 13.Rangachari D. Yamaguchi N. VanderLaan P.A. et al.Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers.Lung Cancer. 2015; 88: 108-111Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar]. The majority of patients with advanced ALK rearranged NSCLC can expect to receive sequential oral TKI monotherapy for prolonged periods of time with reported median overall survival (OS) that exceeds 4 years and nearly half of initially treated patients will be 5-year survivors following diagnosis [14.Rangachari D. Le X. Shea M. et al.Cases of ALK-rearranged lung cancer with 5-year progression-free survival with crizotinib as initial precision therapy.J Thorac Oncol. 2017; 12: e175-e177Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 15.Solomon B.J. Kim D.W. Wu Y.L. et al.Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in ALK-mutation-positive non-small-cell lung cancer.J Clin Oncol. 2018; 36: 2251-2258Crossref PubMed Scopus (252) Google Scholar], a true shit in the natural history of this subtype of lung cancer. However, there is significant heterogeneity in how an individual patient with ALK rearranged tumor will benefit from ALK TKIs and other therapies. A minority of patients can have exceedingly high (>5 years) PFS times with crizotinib [14.Rangachari D. Le X. Shea M. et al.Cases of ALK-rearranged lung cancer with 5-year progression-free survival with crizotinib as initial precision therapy.J Thorac Oncol. 2017; 12: e175-e177Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar] while others can rapidly progress in the central nervous system or systemically with below 1 year in OS times [16.Costa D.B. Shaw A.T. Ou S.H. et al.Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases.J Clin Oncol. 2015; 33: 1881-1888Crossref PubMed Scopus (511) Google Scholar]. This heterogeneity remains unexplained but prevailing hypotheses harken to differences in patient characteristics (smoking status, age, co-morbidities, metabolism of ALK TKIs, immune system status) and more importantly in co-occurring genomic aberrations that can modulate the benefit of ALK TKIs (i.e. can be putative predictive biomarkers) or survival (i.e. can be putative prognostic biomarkers). The latter are of extreme importance not only for ALK rearranged NSCLC—where initial efforts have indicated that even the ALK fusion partner may alter clinical outcomes [17.Lin J.J. Zhu V.W. Yoda S. et al.Impact of EML4-ALK variant on resistance mechanisms and clinical outcomes in ALK-positive lung cancer.J Clin Oncol. 2018; 36: 1199-1206Crossref PubMed Scopus (212) Google Scholar]—but also for other oncogene-driven NSCLCs. As an example, epidermal growth factor receptor (EGFR) mutated NSCLCs are known to harbor a multitude of co-occurring genomic events when analyzed by comprehensive genomic profiling, including mutations in: tumor protein P53 (TP53), phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), Erb-B2 receptor tyrosine kinase 2 (ERBB2), MET proto-oncogene receptor tyrosine kinase (MET) among others [18.VanderLaan P.A. Rangachari D. Mockus S.M. et al.Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: correlation with clinical outcomes.Lung Cancer. 2017; 106: 17-21Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 19.Yu H.A. Suzawa K. Jordan E. et al.Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance.Clin Cancer Res. 2018; 24: 3108-3118Crossref PubMed Scopus (156) Google Scholar]. Some of these co-occurring genomic events can completely abrogate the ability to induce a response to EGFR TKI monotherapy, as in the case of high-level ERBB2 or MET amplification [20.Carney B.J. Rangachari D. VanderLaan P.A. et al.De novo ERBB2 amplification causing intrinsic resistance to erlotinib in EGFR-L858R mutated TKI-naive lung adenocarcinoma.Lung Cancer. 2017; 114: 108-110Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar], while others have less impact on initial EGFR TKI response, as is the case of PIK3CA mutations and heterozygous PTEN mutations [18.VanderLaan P.A. Rangachari D. Mockus S.M. et al.Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: correlation with clinical outcomes.Lung Cancer. 2017; 106: 17-21Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 19.Yu H.A. Suzawa K. Jordan E. et al.Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance.Clin Cancer Res. 2018; 24: 3108-3118Crossref PubMed Scopus (156) Google Scholar]. TP53 mutations in these EGFR mutated cohorts are both predictive of shorter duration of tumor responses to EGFR TKIs and also prognostic of shorter lifespans in these patients [18.VanderLaan P.A. Rangachari D. Mockus S.M. et al.Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: correlation with clinical outcomes.Lung Cancer. 2017; 106: 17-21Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 19.Yu H.A. Suzawa K. Jordan E. et al.Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance.Clin Cancer Res. 2018; 24: 3108-3118Crossref PubMed Scopus (156) Google Scholar]. TP53 mutations are the most common mutations found in NSCLCs and co-occur frequently with driver oncogenes. Indeed, the Lung Cancer Mutation Consortium (LCMC) confirms that TP53 mutations are the most common co-occurring event with EGFR mutations or ALK rearrangements or ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) or other driver alterations; and the presence of TP53 mutations is one of the strongest prognostic markers for shorter survival times in advanced lung cancers [21.Aisner D.L. Sholl L.M. Berry L.D. et al.The impact of smoking and TP53 mutations in lung adenocarcinoma patients with targetable mutations-The Lung Cancer Mutation Consortium (LCMC2).Clin Cancer Res. 2018; 24: 1038-1047Crossref PubMed Scopus (127) Google Scholar]. The underlying biological basis for the prognostic impact of TP53 mutations—a surrogate for P53 protein loss—is still an active area of investigation but it is already known that this tumor suppressor has critical antiproliferative/antiapoptotic functions [22.Olivier M. Hollstein M. Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use.Cold Spring Harb Perspect Biol. 2010; 2: a001008.Crossref PubMed Scopus (1154) Google Scholar], its loss can accelerate the transforming potential of oncogenes in lung cancers [23.Chen Z. Cheng K. Walton Z. et al.A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response.Nature. 2012; 483: 613-617Crossref PubMed Scopus (377) Google Scholar] and its loss can hamper tumor response to TKIs [24.Huang S. Benavente S. Armstrong E.A. et al.p53 modulates acquired resistance to EGFR inhibitors and radiation.Cancer Res. 2011; 71: 7071-7079Crossref PubMed Scopus (94) Google Scholar]. With this background, Kron reports in this issue of Annals of Oncology a detailed analysis of co-occurring mutations in ALK rearranged NSCLC [25.Kron A. Alidousty C. Scheffler M. et al.Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer.Ann Oncol. 2018; 29: 2068-2075Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar]. A total of 216 tumors are analyzed and pathogenic TP53 mutations are identified in close to a quarter (23.8%) of these cancers. Other genomic aberrations using the author's limited gene panel have frequencies below 1%–5%. As seen in the aforementioned cases from the LCMC of co-occurring driver oncogene mutations (in EGFR, ALK, ROS1 and others) with TP53 mutations, the presence of an ALK rearrangement with a TP53 mutation is both predictive of shorter durations of PFS to ALK TKIs and is prognostic for shorter OS times. The authors carry out a detailed statistical analysis that takes into account patient characteristics (age, sex, smoking history, current smoker status, performance status and number of brain metastases), treatment choices (number of treatment lines before crizotinib and number of treatment lines before ceritinib) and the genomic TP53 mutation status. Only current smoker status and TP53 mutations are significant negative prognostic factors for OS in univariate analysis, and merely TP53 mutations remain a negative prognostic factor in multivariate Cox regression analysis. The results highlight the powerful prognostic role of TP53 mutations but it is unclear how they will alter the current treatment paradigms in ALK rearranged NSCLC. Unfortunately, therapeutic efforts to re-establish P53 protein function in cancer have been disappointing and no candidate is available clinically [26.Stiewe T. Haran TE. How mutations shape p53 interactions with the genome to promote tumorigenesis and drug resistance.Drug Resist Updat. 2018; 38: 27-43Crossref PubMed Scopus (72) Google Scholar]. Therefore, the prevailing question remains if a provider will omit the use of an ALK TKI in a tumor with an ALK rearrangement co-occurring with a TP53 mutation? The answer is likely no, as ALK TKIs are significantly superior to other forms of approved NSCLC therapy—be them cytotoxic chemotherapy or immune checkpoint inhibitors—irrespective of TP53 mutational status [27.Solomon B.J. Cappuzzo F. Felip E. et al.Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014.J Clin Oncol. 2016; 34: 2858-2865Crossref PubMed Scopus (194) Google Scholar, 28.Soria J.C. Tan D.S. Chiari R. et al.First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.Lancet. 2017; 389: 917-929Abstract Full Text Full Text PDF PubMed Scopus (786) Google Scholar]. Indeed, worldwide only a fraction of ALK rearranged NSCLCs are diagnosed by comprehensive genomic profiling assays that incorporate analysis of TP53 mutation status [6.VanderLaan P.A. Rangachari D. Majid A. et al.Tumor biomarker testing in non-small-cell lung cancer: a decade of change.Lung Cancer. 2018; 116: 90-95Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 29.DiStasio M. Chen Y. Rangachari D. et al.Molecular testing turnaround time for non-small cell lung cancer in routine clinical practice confirms feasibility of CAP/IASLC/AMP guideline recommendations: a single-center analysis.Clin Lung Cancer. 2017; 18: e349-e356Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. This scenario compiled by the lack of recommendation for TP53 mutation analysis in diagnostic specimens with NSCLC [30.Ettinger D.S. Wood D.E. Aisner D.L. et al.Non-small cell lung cancer, version 5.2017, NCCN Clinical Practice Guidelines in Oncology.J Natl Compr Canc Netw. 2017; 15: 504-535Crossref PubMed Scopus (840) Google Scholar, 31.Lindeman N.I. Cagle P.T. Aisner D.L. et al.Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.J Thorac Oncol. 2018; 13: 323-358Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar] limit the real-world applicability of considering TP53 mutations status as a predictive and prognostic marker in the offices of most oncologists that treat patients with these tumors. Kron concludes their work affirming that 'future clinical trials stratification of this patient subgroup should be considered' and that 'new treatment strategies should be investigated to improve the outcome of ALK/TP53 co-mutated patients' [25.Kron A. Alidousty C. Scheffler M. et al.Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer.Ann Oncol. 2018; 29: 2068-2075Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar]. I agree that as ALK TKI monotherapies improve the duration of control for ALK rearranged NSCLC and novel combination therapies are tested in clinical trials, it may be important to understand prognostic markers such as TP53 mutation status in future trial designs. And I wholeheartedly recommend that the improvement and/or development of therapies for tumors driven by an oncogene with P53 function loss should be prioritized by academic plus pharmaceuticals consortiums evaluating advanced NSCLCs. This work was funded in part through an American Cancer Society grant RSG 11-186 (to DBC) and National Institutes of Health (NIH)/National Cancer Institute (NCI) grant CA218707 (to DBC).