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Table of Contents
MOLECULAR TUMOR BOARD
Year : 2021  |  Volume : 4  |  Issue : 3  |  Page : 541-546

Concurrent EGFR and PIK3CA mutations in non-small-cell lung cancer


1 Department of Medical Oncology, Mahamana Pandit Madan Mohan Malviya Cancer Center, and Homi Bhabha Cancer Hospital, Tata Memorial Center, Varanasi, Uttar Pradesh, India
2 Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Molecular Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, India
4 Department of Medical Oncology, Mahavir Cancer Sansthan, Patna, Bihar, India
5 Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Submission27-Aug-2021
Date of Decision04-Sep-2021
Date of Acceptance18-Sep-2021
Date of Web Publication08-Oct-2021

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_207_21

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How to cite this article:
Kapoor A, Noronha V, Shetty OA, Kashyap L, Kumar A, Chandrani P, Patil VM, Joshi A, Menon N, Kumar R, Pragya R, Prabhash K. Concurrent EGFR and PIK3CA mutations in non-small-cell lung cancer. Cancer Res Stat Treat 2021;4:541-6

How to cite this URL:
Kapoor A, Noronha V, Shetty OA, Kashyap L, Kumar A, Chandrani P, Patil VM, Joshi A, Menon N, Kumar R, Pragya R, Prabhash K. Concurrent EGFR and PIK3CA mutations in non-small-cell lung cancer. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Dec 9];4:541-6. Available from: https://www.crstonline.com/text.asp?2021/4/3/541/327790




  Case Summary Top


History and examination

A 43-year old female patient with no history of smoking and no comorbidities presented with a 1-month history of progressive cough, weight loss, and chest pain. She had an Eastern Cooperative Oncology Group performance score of 1. There were diminished breath sounds in the left lower zone, and the liver was palpable 4 cm below the right costal margin.

Investigations

Contrast-enhanced computed tomography scan showed 5.6 cm × 4.5 cm pulmonary mass in the left lower lobe and multiple nodular opacities scattered in bilateral lung fields along with lesions in both lobes of the liver, the largest being 7 cm in right lobe [Figure 1]a and [Figure 1]b. Ultrasound-guided biopsy from the liver lesion was suggestive of TTF1-positive metastatic adenocarcinoma of the lung.
Figure 1: The left panel shows the liver lesion while the right panel shows the lung window of the scans at different time points. (a and b) The baseline imaging prior to starting gefitinib, (c and d) the progression on gefitinib, while (e and f) the partial response to four cycles of chemotherapy (pemetrexed and carboplatin)

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Molecular testing

The tissue biopsy was subjected to molecular testing. Real-time polymerase chain reaction was positive for a mutation in the epidermal growth factor receptor (EGFR) exon 19 deletion; anaplastic lymphoma kinase by Ventana D5F3 antibody immunohistochemistry (IHC) was negative. Programmed death ligand (PD-L1) by Ventana SP263 IHC was also negative.

Further therapy

Due to financial constraints, she was started on a first-generation EGFR tyrosine kinase inhibitor (TKI) gefitinib, on which she had a partial remission at the first response scan done at 3 months but progressed at multiple sites at 5 months [Figure 1c and d]. A repeat liver biopsy was performed; however, sufficient tumor tissue was not available. Peripheral blood sample for cell-free deoxyribonucleic acid (cfDNA) revealed wild-type EGFR. She was started on palliative intent combination chemotherapy with pemetrexed and carboplatin. Post four cycles of chemotherapy, the scan showed partial response [Figure 1e and f] and she was started on maintenance pemetrexed. However, she progressed in the liver and brain after eight cycles of maintenance pemetrexed and a repeat biopsy was performed from the liver. The biopsy showed metastatic deposits of adenocarcinoma; the tissue was not subjected to repeat IHC to preserve it for molecular testing.

Next-generation sequencing

Next-generation sequencing (NGS) testing was done on the repeat biopsy tissue. This assay is designed for the evaluation of DNA variants and fusion transcripts using the targeted gene panel, SOPHiA Solid Tumor Plus Solution, which identifies single-nucleotide variants, indels from 42 genes, 139 RNA fusions, gene amplification events in 24 genes, and MSI status (6 unique loci). After the library preparation of extracted DNA and RNA, paired-end sequencing was performed by synthesis technology on the Illumina MiSeq platform. SOPHiA DDM software was used for data analysis. The alterations identified in various genes are depicted in [Table 1].
Table 1: Alterations identified in the next.generation sequencing done on the repeat tissue biopsy at progression

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Thus, the NGS data revealed clinically relevant alterations in three genes, i.e.; EGFR, PIK3CA, and TP53. Of these, alterations in the EGFR and PIK3CA were noted to be targetable with available drugs.


  Excerpts from Discussion in the Molecular Tumor Board Top


The most frequent oncogenic mutation in non-small cell lung carcinomas (NSCLC) is the EGFR tyrosine kinase-activating mutation.[1] This mutation is commonly observed in exons 18, 19, 20, and 21.[2] The EGFR exon 19 in frame deletion between codons 747 and 750 was observed in the present case at a variant allelic frequency (VAF) of 36.8%. The in-frame deletion observed at this region is the most common one occurring at a frequency of 50%–60% among all the classic EGFR mutations and hence this alteration was classified as a Tier I variant.[2] This alteration has been consistently reported to have better outcomes with EGFR TKIs as compared to chemotherapy.

The second actionable alteration observed was in the PIK3CA gene in exon 20 with a VAF of 24.4%. The alteration observed was the non-synonymous single-nucleotide substitution, c.3129 G>A, M1043I. This results in activation of the PI3K/AKT/mTOR signaling pathway to promote cell proliferation and portends a poor prognosis.[3] The alteration observed in this case confers a gain of function effect to the PIK3CA protein. PI3K inhibitors (alpelisib) have been approved by the United States Food and Drug administration (US-FDA) in PIK3CA mutant hormone receptor-positive advanced breast cancers.[4] However, there are no studies that have described this alteration as one that confers resistance to EGFR TKIs and hence the M1043I alteration observed in this case was classified as a Tier II variant.

The third alteration detected in the DNA-binding domain of the TP53 gene is an insertion-deletion mutation between codons 704 and 709 of TP53, which is a negative prognostic factor. Epigenetic and genetic changes frequently lead to p53 pathway inactivation in lung cancer (in ~50% in NSCLC), more so in squamous cell carcinomas, and are an early event in lung carcinogenesis.[3] However, the mutation observed in this case has not been frequently reported in the literature and hence this has been classified as a Tier III variant, i.e., a variant of uncertain clinical significance. Several studies have suggested that the TP53 mutation occurring alone or concomitantly with the EGFR exon 19 deletion is associated with resistance to all lines of therapy including EGFR TKIs.[1],[2],[3] It should be noted that the coexistence of alterations in the DNA-binding domain of TP53 (between exons 5–8) and EGFR exon 19 deletion warrants an aggressive therapeutic approach and should be closely monitored.

The Molecular Tumor Board recommended the use of alpelisib on compassionate basis after exhausting the standard lines of therapy. In addition, since there was no EGFR exon 20 T790M mutation detected, and since the patient had already progressed on gefitinib, additional EGFR-directed therapy was not advised. The patient has been planned for whole brain radiotherapy followed by second-line docetaxel chemotherapy as per the standard-of-care therapy.[1]


  Discussion Top


EGFR is one of the closely related tyrosine kinase receptors of erbB family, which includes erbB1 (also known as EGFR), erbB2 (HER2), erbB3, and erbB4 sharing a similar basic structure. Each of these receptors possesses exclusive properties along with a variation in the tyrosine kinase activity.[2],[3] EGFR undergoes conformational change on ligand binding (e.g., epidermal growth factor) leading to intracellular domain phosphorylation and subsequent downstream signaling by various pathways. Depending on the pathway, the result could be cell multiplication or evasion of apoptosis.[2] A broad panel genome sequencing can lead to the detection of more than one driver mutation in a particular patient. The studies of exclusive cancer driver genes and the pathways associated with the genes as the etiopathogenesis of the disease have helped in establishing the therapeutic role of molecular-targeted drugs and have helped define personalized therapy.

As demonstrated in previous studies, squamous cell carcinoma of the lung harbors the PIK3CA mutation with a frequency of 11.4% as against adenocarcinoma in which PIK3CA mutation is noted at a frequency of 2.8%–7%.[3],[4] The preclinical data suggest that concomitant EGFR and PIK3CA mutations in lung cancer confer resistance to EGFR TKI therapy resulting in a poor prognosis.[5] PIK3CA mutations are mostly seen at hotspots in exons 9 and 20, which encode the helical and kinase domains of p110α, the catalytic subunit of the PI3K enzyme.[6] These mutations result in successive activation of PI3K activity, phosphorylation of AKT, and stimulation of mTORC1, which are mandatory for cell survival and growth. Through comprehensive molecular profiling, it has been observed that PIK3CA mutation is seen in most of the lung cancers, in which a genomic alteration is noted in more than one oncogene.[7] In an artificial setup, downregulation of the PI3K pathway is associated with TKI sensitivity in EGFR-mutant lung cancer cell lines.[8] A preclinical study noted that PIK3CA p.E545K mutation when introduced in exon 9 in an EGFR exon 19 deleted HCC827 cell line led to resistance to gefitinib.[9] Furthermore, reinstating the PI3K pathway by an PIK3CA mutation has been described as a modality for acquired resistance to EGFR TKI in EGFR-mutant lung cancer.[6] For example, in HER2-positive breast cancers, the PIK3CA mutation is associated with lower complete response rates and shorter disease-free survival after HER2-directed neoadjuvant therapy.[10],[11],[12] While the patients with double-mutations (EGFR-mutant/PIK3CA-mutant) discontinued therapy within 2 years, about one-third of patients having a single mutation (EGFR-mutant/PIK3CA wild-type) continued on treatment for an additional 1 year.[13] This study reported that in patients with EGFR-mutant, or KRAS-mutant lung cancer, a concurrent PIK3CA mutation led to a significant decrease in median overall survival (OS, 18 months vs. 33 months without PIK3CA mutation, P = 0.006).[13] In addition, complete responses were noted exclusively in patients with single-mutation cancers.

PIK3CA mutation is, in fact, the most common coexisting mutation along with other driver mutations in NSCLC.[10],[13] This was established by the French NCI's Lung Cancer Mutation Consortium, which collected the tissues from 10,000 patients with NSCLC for analysis.[14] In a study by Sequist et al., the PIK3CA mutation was also associated with acquired resistance to EGFR TKIs.[10] The same study reported that after the acquisition of T790M mutations (49%) and small cell transformation (14%), PIK3CA mutation (5%) and MET amplifications (5%) were the most common resistance mechanism to EGFR TKIs.[15],[16] Another point worth highlighting is the attrition of the tissue after histopathological examination and EGFR testing. In the IPASS study, only 36% patients' tissue was found to be adequate for EGFR testing.[17] Thus, after testing for EGFR, it is expected that the tissue will be depleted and will be inadequate for testing for PIK3CA. With the increasing use and availability of NGS, it has become possible to do parallel testing for multiple mutations and also to increase the sensitivity of the detection.[18]

The mutation profile in Asian patients particularly Indian patients is different from that reported in the Western literature. In various studies from the Tata Memorial Center, EGFR mutation and KRAS mutation have been reported among 23% and 18% Indian patients, respectively, as compared to 10%–15% and 25%–50%, respectively, among Western patients.[15],[16] In patients with squamous cell carcinoma of the lung, Joshi et al. have reported targetable molecular alterations in FGFR1 (14%), EGFR (5.8%), and PIK3CA (5.5%) genes among Indian patients.[17]

In a meta-analysis by Wang et al., it was reported that PIK3CA mutation had no significant correlation with age, gender, stage, or the smoking status of the patient.[19] In another study by Zhang et al., the PIK3CA mutation was found to be strongly associated with lymph node metastasis (with relative risk of 2.8; 95% CI, 1.1–7.1; P = 0.029).[20] This is postulated to occur due to an increased ability of the tumor cells to invade the lymphatic system as a result of a mutation in the PIK3CA pathway.

Multiple studies have failed to uncover any prognostic implications of the PIK3CA mutation in terms of survival for patients with advanced NSCLC. However, two studies by Zhang et al. and Song et al., both of which enrolled patients with adenocarcinoma of the lung undergoing surgical resection, reported significantly poor progression-free survivals (PFS) and OS in the presence of a PIK3CA mutation.[20],[21] The meta-analysis by Wang et al. also reported a significantly poor OS (HR, 1.55; 95% CI, 1.13–2.13; P = 0.007) and PFS (HR, 1.48; 95% CI, 1.06–2.08; P = 0.023) with PIK3CA mutations based on the above two studies.[19]

Although it seems that the PIK3CA mutation is not directly associated with the overall prognosis in patients with advanced lung cancer, there are some data to suggest it may predict poorer efficacy of EGFR TKIs in patients harboring a PIK3CA mutation in addition to the EGFR mutation. This was first explored by Ludovini et al.,[22] who described a shorter time to progression (median 2.3 vs. 6.0 months; P = 0.01) and OS (median 9.9 vs. 30.2 months; P < 0.001) in 6 patients harboring a PIK3CA mutation treated with first-generation EGFR TKIs. However, it should be noted that only 2 out of 6 patients (33.3%) had concurrent EGFR sensitizing mutations, as the study included patients who were unselected for the EGFR mutation status.

Eng et al. observed that concurrent PIK3CA mutations along with EGFR mutations led to a lower objective response rate (62% vs. 83%; P = 0.80) and shorter time to progression (median 7.8 vs. 11.1 months; P = 0.84) to EGFR TKIs, but the data did not reach statistical significance.[13] In a contrasting report of 54 patients with EGFR-mutant advanced NSCLC, the presence of concurrent PIK3CA mutations was found to be significantly associated with a longer PFS when compared to wild-type PIK3CA.[20] Thus, it seems that contrasting prognostic data are available for the presence of PIK3CA mutations that occur concurrently with EGFR mutations. When the data were further analyzed, it was hypothesized that the effect of the PIK3CA mutation on the PFS was domain-dependent. The domains associated with the p85 binding domain (R88Q, R108H, and K111E) were related to an improved PFS, while mutations in the kinase (Y1021H and H1047R), helical (E542K), and C2 (N345K) domains were found to be linked to a worse PFS. This perhaps explains the contradictory results in the different studies.[20],[23]

There are extremely limited data on the use of PIK3CA inhibitors like alpelisib in PIK3CA mutant lung cancer. In a Japanese Phase I study that included multiple solid tumors including NSCLC, the objective response rate, disease control rate, and median PFS with alpelisib dosed at 350 mg/day were reported to be 3%, 57.6%, and 3.4 months, respectively.[24] [Table 2] summarizes studies involving patients with PIK3CA-mutant NSCLC. A Phase Ib study combined buparlisib (a pan class I PI3K3 inhibitor) with gefitinib and reported that the maximal therapeutic doses were gefitinib 250 mg and buparlisib 80 mg/day.[25] Antitumor activity was observed with addition of buparlisib in EGFR TKI-resistant patients. An in vivo study suggested that inhibitors of the PI3K-mTOR pathway may be active in cancers with PIK3CA mutations and, when combined with MEK inhibitors, may effectively treat KRAS mutated lung cancers.[26] The recommendation of the Molecular Tumor Board in this case was solely considered appropriate based on the patient's molecular profile and the phase I data encompassing multiple solid tumors. In addition, although the data are scarce, it is suggested that patients harboring concurrent EGFR and PIK3CA mutations at the baseline, if being treated with a first-generation oral EGFR TKI due to financial constraints, should be offered a combination of gefitinib plus chemotherapy. This approach may overcome the resistance to EGFR TKIs, if any, conferred by concurrent PIK3CA mutation.[27] This case highlights the gap in our knowledge about the various treatment options for patients with a similar mutation profile and this emphasizes the urgent need for studies in this regard.
Table 2: Studies involving patients with non-small-cell lung carcinomas harboring a PIK3CA mutation

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  Conclusions Top


The available literature on PIK3CA mutations in NSCLC suffers from limited sample size, leading to inconsistent results. There is an urgent need for further studies on the effect of mutations in different domains of the PIK3CA mutations and their influence on EGFR-TKI efficacy. At present, it seems appropriate to continue offering single agent EGFR TKI, or gefitinib plus chemotherapy in patients with concurrent EGFR and PIK3CA mutation, with consideration of the use of PIK3CA inhibitors in later lines on compassionate basis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Eng J, Woo KM, Sima CS, Plodkowski A, Hellmann MD, Chaft JE, et al. Impact of concurrent PIK3CA mutations on response to EGFR tyrosine kinase inhibition in EGFR-mutant lung cancers and on prognosis in oncogene-driven lung adenocarcinomas. J Thorac Oncol 2015;10:1713-9.  Back to cited text no. 13
    
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