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Table of Contents
LETTER TO THE EDITOR
Year : 2021  |  Volume : 4  |  Issue : 4  |  Page : 797-799

PIK3CA alterations in non-small cell lung carcinoma: A puzzle yet to be solved


Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India

Date of Submission04-Nov-2021
Date of Decision11-Nov-2021
Date of Acceptance24-Nov-2021
Date of Web Publication29-Dec-2021

Correspondence Address:
Prabhat Singh Malik
Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_260_21

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How to cite this article:
Baa AK, Malik PS. PIK3CA alterations in non-small cell lung carcinoma: A puzzle yet to be solved. Cancer Res Stat Treat 2021;4:797-9

How to cite this URL:
Baa AK, Malik PS. PIK3CA alterations in non-small cell lung carcinoma: A puzzle yet to be solved. Cancer Res Stat Treat [serial online] 2021 [cited 2022 Jan 21];4:797-9. Available from: https://www.crstonline.com/text.asp?2021/4/4/797/334205



Kapoor et al. have highlighted the gap to be bridged in terms of management of co-mutations in advanced non-small cell lung carcinoma (NSCLC).[1] Phosphoinositide-3-kinase catalytic alpha polypeptide (PIK3CA) mutations occur in the helical-binding domain and the catalytic subunit of the protein. These rearrangements have tumorigenic potential and impart resistance to treatment.[2] PIK3CA (exons 9 and 20) mutations generally exist in conjunction with other molecular alterations in genes such as the epidermal growth factor receptor (EFGR), Kirsten rat sarcoma virus (KRAS), anaplastic lymphoma kinase (ALK), and phosphatase and tensin analog (PTEN).[3],[4]

Asian literature reports that EFGR/PIK3CA co-mutations are more prevalent than KRAS/PIK3CA co-mutations, probably because of the higher incidence of EFGR mutations seen in the Eastern population as compared to the Western.[5] EGFR/PIK3CA co-mutations are more common with squamous than with adenocarcinoma histology (5%–10% vs. 3%)[3] and generally occur in female patients aged less than 60 years in the absence of smoking.[1],[3] We queried the recent targeted sequencing data of 604 lung adenocarcinomas from MSK-IMPACT through cBioPortal to check for the presence of PIK3CA alterations along with alterations in EGFR, KRAS, and ALK [Figure 1].The lollipop graph demonstrates the missense, truncated, and fusion mutations, with exon 9 E454K mutation being frequently encountered. The Oncoprint plot shows a 6% incidence of PIK3CA mutations along with other alterations; notable is the tumor mutational burden which appears to be higher in this group.
Figure 1: cBioportal analysis. (a) Distribution and frequency of phosphoinositide-3-kinase catalytic alpha polypeptide (PIK3CA) co-mutations. (b) Oncoprint plot

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Intra-tumoral heterogeneity results from the complex interplay of genetic and epigenetic changes with protein modification process, resulting in subclonal evolution and branching mutations that subsequently cause resistance. Common resistance mechanisms for anti-EGFR therapy are the development of the T790M mutation (50%-60%), MET amplification (5–20%),[6] C797S mutation, and phenotypic conversion to small cell lung cancer due to the loss of TP53 and RB1.[7] PIK3CA mutations/amplifications are the known mechanisms of resistance against EGFR-tyrosine kinase inhibitors (TKIs).[2] Historically, this subtype responds poorly to TKIs and may have led to shorter progression-free survival.[1],[3] TP53 mutation often occurs with PIK3CA mutation, imparting resistance, although it has been reported as a variant of uncertain significance in the present case. It is unknown whether the PIK3CA mutation detected in Kapoor et al.'s case was gained secondarily or was a primary one. This emphasizes the need for comprehensive mutational profiling at baseline for better clarity and therapeutic decision-making.

We are of the opinion that anti-angiogenic agents (bevacizumab/ramucirumab) and immunotherapy in addition to chemotherapy could be a therapeutic choice. This was proven in the IMpower150 study, where the administration of atezolizumab + bevacizumab + carboplatin + paclitaxel regimen led to a survival benefit after failure of TKIs; although this was based on the subgroup analysis.[8],[9] Targeting PIK3CA alterations with various class I PI3K inhibitors in NSCLC has not been successful. Trials with alpelisib in PIK3CA-mutant NSCLC are underway.[10]

In the absence of such data, we would avoid using alpelisib in this patient over chemotherapy and antiangiogenic agents with or without immunotherapy. Indeed, our analysis and that of Lage et al.'s suggest that patients having PIK3CA alterations tend to have a higher tumor mutational burden.[4] Hence, we postulate that they may be better candidates for an immunotherapeutic approach in combination with chemotherapy. This could be a possible research question needing validation in a clinical trial.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kapoor A, Noronha V, Shetty OA, Kashyap L, Kumar A, Chandrani P, et al. Concurrent EGFR and PIK3CA mutations in non-small-cell lung cancer. Cancer Res Stat Treat 2021;4:541-6.  Back to cited text no. 1
  [Full text]  
2.
Chaft JE, Arcila ME, Paik PK, Lau C, Riely GJ, Pietanza MC, et al. Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling. Mol Cancer Ther 2012;11:485-91.  Back to cited text no. 2
    
3.
Qiu X, Wang Y, Liu F, Peng L, Fang C, Qian X, et al. Survival and prognosis analyses of concurrent PIK3CA mutations in EGFR mutant non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors. Am J Cancer Res 2021;11:3189-200.  Back to cited text no. 3
    
4.
Analysis Identifies Frequency of PI3K Pathway Alterations in Patients with NSCLC – The ASCO Post. Available from: https://ascopost.com/news/march-2021/analysis-identifies-frequency-of-pi3k-pathway-alterations-in-patients-with-nsclc/. [Last accessed on 2021 Oct 29].  Back to cited text no. 4
    
5.
Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, Prabhash K. Epidermal growth factor receptor-mutated non-small-cell lung cancer: A primer on contemporary management. Cancer Res Stat Treat 2019;2:36-53.  Back to cited text no. 5
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6.
Kapoor A, Noronha V, Chougule A, Patil VM, Menon N, Joshi A, et al. Molecular tumor board: Case 1-Interplay of EGFR, MET and PD-L1 in non-small cell lung carcinoma. Cancer Res Stat Treat 2019;2:228-31.  Back to cited text no. 6
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7.
Bondili SK, Nandhana R, Noronha V, Joshi A, Patil V, Menon N, et al. Resistance mechanisms to epidermal growth factor receptor inhibitors in non-small cell lung cancer. Cancer Res Stat Treat 2020;3:801-7.  Back to cited text no. 7
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8.
Tomasini P, Brosseau S, Mazières J, Merlio JP, Beau-Faller M, Mosser J, et al. EGFR tyrosine kinase inhibitors versus chemotherapy in EGFR wild-type pre-treated advanced nonsmall cell lung cancer in daily practice. Eur Respir J 2017;50:1700514.  Back to cited text no. 8
    
9.
Reck M, Mok TS, Nishio M, Jotte RM, Cappuzzo F, Orlandi F, et al. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): Key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med 2019;7:387-401.  Back to cited text no. 9
    
10.
A Phase II, Open Label, Multiple Arm Study of AUY922, BYL719, INC280, LDK378 and MEK162 in Chinese Patients with Advanced Non-small Cell Lung Cancer-Full Text View. Available from: https://clinicaltrials.gov/ct2/show/NCT02276027. [Last accessed on 2021 Oct 29].  Back to cited text no. 10
    


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