author: collin m. blakely1,2 · 2019. 10. 12. · 1 title: a new pathway emerges to interpret lung...

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Title: A new pathway emerges to interpret lung cancer genomic alterations

Author: Collin M. Blakely1,2 Author Affiliations: 1Department of Medicine, University of California, San Francisco, 2Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco Contact Information: Email: [email protected] Address: 550 16th Street, 6536 San Francisco, CA 94158 Phone: 415-502-6959 Conflicts of interest: C.M.B receives research funding from AstraZeneca, Novartis, Spectrum, Mirati, MedImmune, Incyte, Roche, and Takeda. C.M.B performs consulting for Revolution Medicines. Running Title: A new pathway for lung cancer genomics Funding: C.M.B. receives funding from the Damon Runyon Cancer Research Foundation, the Doris Duke Charitable Foundation, and the V Foundation.

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Summary: The clinical utility of performing tumor genetic testing to assess for alterations beyond the known

targetable oncogenes in lung adenocarcinoma is unclear. Analyzing cancer pathway alterations

beyond single oncogenic driver mutations in addition to markers of tumor mutation burden and

genomic instability may provide additional predictive and prognostic information.




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Main Text:

In this issue of Clinical Cancer Research, Zhou and colleagues (1) analyzed targeted next

generation sequencing data (MSK-IMPACT) from 492 surgically resected early stage lung

adenocarcinoma samples and correlated their findings with the clinical outcome of disease-free

survival (DFS). Rather than focusing on specific genetic alterations, the authors used

a pathway-centric approach that they previously defined by analysis of The Cancer Genome

Atlas (TCGA) (2) to identify mutation patterns that fit within 10 canonical cancer-

related pathways, including: 1) cell cycle, 2) Hippo, 3) Myc, 4) Notch, 5) oxidative stress

response/Nrf2, 6) PI3K, 7) receptor-tyrosine kinase (RTK)/RAS/MAPK, 8) TGFβ, 9) p53, and

10) β-catenin/Wnt. For each tumor they calculated the number of pathways altered (NPA),

the tumor mutation burden (TMB) and the fraction of the genome altered (FGA). They found that

the NPA correlated with DFS in a multivariate analysis, and that cell cycle, Hippo, TGFβ, and

p53 pathway alterations in particular were associated with increased risk of disease recurrence.

Next generation sequencing through the use of targeted exome panels is a mainstay of

clinical testing for advanced lung adenocarcinomas and is critical for the identification of

targetable oncogenic driver mutations. The development of EGFR inhibitors in the early 2000’s

led to the discovery of activating mutations within EGFR as an important predictor of response

to EGFR tyrosine kinase inhibitors (TKIs), ushering in the era of tumor genetic testing for lung

cancer. The success of EGFR testing as a predictive biomarker of response to EGFR TKI

treatment led to a hunt for other tumor genetic alterations that may similarly predict targeted

therapy responses or identify targets for drug development. This led to a relative explosion of

targetable oncogenic alterations in lung adenocarcinoma, including: ALK, ROS1, RET, and

NTRK rearrangements as well as somatic variants in BRAF, MET, and now KRAS. The

multitude of targetable oncogenic drivers in lung adenocarcinoma has led to single-gene assays

becoming relatively obsolete, with a significant portion of tumor genetic testing now being




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performed by next-generation sequencing panels. These next-generation sequencing panels

typically cover the coding regions of dozens if not hundreds of cancer-related genes, well-

beyond the current known targetable alterations. To this point, the importance of non-

targetable, so-called ‘passenger’ alterations as predictive or prognostic biomarkers is unknown.

New studies are beginning to shed light on the role of these co-occurring genomic alterations.

The clinical significance of co-occurring genomic alterations in 10 cancer related

pathways was assessed in early stage lung cancer(1). Intriguingly, they found that the NPA

present in a tumor was independently associated with DFS, and that alterations in cell cycle,

Hippo, TGF, and p53 pathways in particular were associated with early relapse of lung

adenocarcinoma, suggesting potential avenues for pharmacologic intervention. Notably, the

frequency of alterations in known oncogenic drivers, including KRAS, EGFR, and ALK was

similar to what would be expected for advanced lung adenocarcinoma, suggesting that genomic

alterations identified in early stage lung cancers are likely to be relevant to patients with

advanced disease. Additionally, 84% of tumors analyzed harbored genomic alterations in the

RAS/RTK pathway confirming that the vast majority of lung adenocarcinomas are driven by

oncogenic activation of the RAS/MAPK signaling pathway. Clinically, these alterations can be

addressed by many of the targeted therapies that have been developed and have shown clear

benefit for patients. However, as the benefits of these therapies are transient and not curative,

their utility in early stage disease is still unproven. Understanding the biological and clinical

significance of secondary pathway alterations is critical to devising new strategies to combat

both early and advanced stage lung adenocarcinoma.

Many of the pathways associated with decreased DFS in early stage lung

adenocarcinoma have also been shown to correlate with poor response to targeted therapies in

advanced stage disease. Genetic alterations in cell cycle genes correlated with poor response

to the third generation EGFR inhibitor osimertinib in a study of cell-free DNA from over 1,000

advanced EGFR-mutant lung cancer cases (3). Whether cell cycle alterations similarly affect




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response to other TKIs is unknown, as is the mechanism underlying this effect. The study by

Zhou et al., suggests that cell cycle alterations may promote increased genomic instability and

copy-number alterations, which may in turn account for poor DFS in early stage lung cancer and

TKI resistance in advanced stage disease. Whether cell cycle alterations are the cause of

genomic instability, or simply a marker for it, is unclear and further investigation is needed.

Cell cycle pathway alterations frequently co-occurred with p53 pathway alterations,

which were also correlated with decreased DFS in patients with resected lung

adenocarcinomas. Both cell cycle and p53 pathway alterations were associated with an

increase in the fraction of the genome altered (FGA), which itself correlates with poor DFS in

this study(1). This serves as a confirmation of the findings from TRACERx, which showed that

elevated copy-number heterogeneity was associated with increased risk of non-small cell lung

cancer recurrence or death (4). Lung adenocarcinomas that harbor both cell cycle and p53

pathway alterations appear to be at high risk for genomic instability, which in turn may promote

early recurrence for patients with early stage disease or resistance to targeted therapy for

patients with advanced disease (5).

Genetic alterations in the Hippo and TGF pathway were also associated with inferior

DFS. Hippo signals primarily through its effectors Yes-Activated Protein (YAP) and TAZ, whose

activities have been implicated in resistance to EGFR and BRAF targeted therapies (6) as well

in promoting immune evasion through upregulation of Programmed Death-Ligand 1 (PD-L1) (7).

Intriguingly, tumors with genetic alterations in the Hippo pathway were also associated with

higher tumor mutation burden(1). Given that PD-L1 expression and TMB have both been

shown to be independent predictors of response to immune checkpoint inhibitor (ICI) therapy,

these findings suggest that tumors with Hippo pathway alterations may be more likely to

respond to ICI and less likely to respond to targeted therapies.

The role of tumor genomics in informing clinical decisions for the treatment of lung

adenocarcinomas has evolved from single gene assays to multi-gene panels and now to broad




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next-generation sequencing panels that include upwards of several hundred genes. While the

primary goal of these assays is to identify single targetable oncogenes in the RTK/RAS

pathway, the study by Zhou and colleagues demonstrates that additional prognostic and

potentially predictive information may be gleaned by analyzing NPA, FGA, and TMB as well as

which specific pathways are altered (Figure 1). Clinical trials should be considered to determine

whether patients with early stage lung cancer with elevated NPA or FGA may be more likely to

benefit from adjuvant therapy, and whether those with elevated TMB and/or Hippo pathway

alterations are more likely to benefit from treatment that includes an ICI. Similarly, clinical trials

should be considered for patients with advanced lung adenocarcinomas with a targetable

oncogenic driver mutation to determine whether there is clinical benefit to combination therapies

that target co-occurring cell cycle (CDK4/6 inhibitor) and/or p53 (MDM2 inhibitor) pathway

alterations.

Figure Legend:

Figure 1. Potential role for tumor genomic pathway analysis in treatment decisions for

lung adenocarcinoma patients. (A) Initial analysis of tumor genetic information should

focus on identifying targetable oncogenic driver mutations in EGFR, KRAS, BRAF, MET

and fusions involving ALK, ROS1, RET, and NTRK. Additional prognostic and predictive

information may be gained by analyzing broad tumor genomic features including tumor

mutation burden (TMB) and fraction of the genome altered (FGA). (B) Analysis of the

number of cancer-related pathways altered (NPA) as well as which specific pathways

are altered may help guide the most appropriate therapy for the patients. (C) Therapy

may include single agent or combination therapies consisting of targeted therapy,

immunotherapy, or chemotherapy. Ultimately, clinical trials will need to be performed to




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determine the most effective therapies for specific patterns of tumor genomic

alterations.

References

1. Zhou J, Sanchez-Vega F, Caso R, Tan KS, Brandt WS, Jones GD, et al. Analysis of Tumor Genomic Pathway Alterations Using Broad-Panel Next Generation Sequencing in Surgically Resected Lung Adenocarcinoma. Clin Cancer Res 2019 doi 10.1158/1078-0432.CCR-19-1651.

2. Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, et al. Oncogenic Signaling Pathways in The Cancer Genome Atlas. Cell 2018;173(2):321-37 e10 doi 10.1016/j.cell.2018.03.035.

3. Blakely CM, Watkins TBK, Wu W, Gini B, Chabon JJ, McCoach CE, et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat Genet 2017;49(12):1693-704 doi 10.1038/ng.3990.

4. Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, et al. Tracking the Evolution of Non-Small-Cell Lung Cancer. 2017;376(22):2109-21 doi 10.1056/NEJMoa1616288.

5. Aisner DL, Sholl LM, Berry LD, Rossi MR, Chen H, Fujimoto J, 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(5):1038-47 doi 10.1158/1078-0432.CCR-17-2289.

6. Lin L, Sabnis AJ, Chan E, Olivas V, Cade L, Pazarentzos E, et al. The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat Genet 2015;47(3):250-6 doi 10.1038/ng.3218.

7. Janse van Rensburg HJ, Azad T, Ling M, Hao Y, Snetsinger B, Khanal P, et al. The Hippo Pathway Component TAZ Promotes Immune Evasion in Human Cancer through PD-L1. Cancer Res 2018;78(6):1457-70 doi 10.1158/0008-5472.CAN-17-3139.




© 2019 American Association for Cancer Research© 2019 American Association for Cancer Research

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Published OnlineFirst October 14, 2019.Clin Cancer Res Collin M. Blakely alterationsA new pathway emerges to interpret lung cancer genomic

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author: collin m. blakely1,2 · 2019. 10. 12. · 1 title: a new pathway emerges to interpret lung...

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