Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease. Approximately 92% of patients with PDAC will die with advanced disease within 5 years of diagnosis when accounting for all disease stages.1 Despite recent incremental advances in the treatment of metastatic PDAC with 5-fluorouracil (5FU), irinotecan, oxaliplatin, and leucovorin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel, median survival remains <1 year.2,3 Moreover, second-line treatment options are of limited benefit, and the use of immunotherapies and molecularly targeted drugs has proven disappointing. Widespread use of genomic analysis to identify actionable mutations in PDAC has been constrained due to challenges with tissue acquisition and the low likelihood of identifying an actionable target. Although recent studies indicate that genomic analysis is technically feasible in most patients with PDAC, more information is needed to determine whether these tumors respond to targeted therapy when actionable mutations are identified.4 This report describes a patient with PDAC whose tumor was characterized by an exon 19 deletion and who experienced a sustained response to erlotinib.
Case Summary
A 57-year-old Caucasian man with type II diabetes mellitus presented with increasing insulin requirements, jaundice, and weight loss. Imaging revealed a pancreatic head mass with <180° of superior mesenteric vein abutment and no evidence of distant metastases. A biopsy confirmed PDAC. He received 6 cycles of neoadjuvant FOLFIRINOX followed by pancreaticoduodenectomy with negative margins and 6 cycles of adjuvant FOLFIRINOX. Surgical pathology revealed ypT3N1Mx (stage IIB) adenocarcinoma.
Eight months after completion of adjuvant therapy, PET imaging revealed recurrent disease in the postsurgical bed and multiple liver metastases. He began gemcitabine and nab-paclitaxel for metastatic PDAC, but after 54 weeks imaging revealed progression of hepatic metastases. Subsequently, he was treated with second-line FOLFIRINOX. After 38 weeks, imaging again showed progression of hepatic metastases. He received third-line therapy with docetaxel and irinotecan for 2 weeks, but this therapy was complicated by febrile neutropenia.
A tumor specimen from the pancreaticoduodenectomy was sent to Foundation Medicine (Cambridge, MA) for genomic analysis, which revealed an activating mutation in exon 19 (L747_P753>S) of EGFR with a mutation allele frequency (MAF) of 16%. Mutations were also detected in CDKN2A (splice site 144_153del10) with an MAF of 15%, TP53 (F113C) with an MAF of 7%, and amplifications of PRKCI and TERC. After the sequencing results, he began erlotinib at 150 mg daily. He subsequently developed grade 2 acneiform drug eruption, which responded to triamcinolone and doxycycline. CT imaging revealed a partial response (PR) by RECIST at 8 and 24 weeks after starting erlotinib. His CA 19-9 level declined from 29,156 to 387 U/mL at 24 weeks (Figure 1). At 32 weeks, imaging showed a sustained PR, although his CA 19-9 level increased to 778 U/mL. At 40 weeks, his CA 19-9 level had increased to 3,847 U/mL and CT imaging revealed unequivocal disease progression by RECIST, with increasing size and number of hepatic metastases.
After disease progression on erlotinib, a repeat liver biopsy revealed an EGFR T790M mutation by TaqMan assay (Applied Biosystems, Foster City,
Timeline for the CA 19-9 tumor marker over the past 20 months. The area highlighted in green, starting at month 4, represents the period on erlotinib therapy. The period after the green box represents the time on osimertinib.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 9; 10.6004/jnccn.2017.0151
Discussion
This case describes a patient with metastatic PDAC and an activating EGFR mutation that had a partial and sustained response to erlotinib monotherapy followed by T790M resistance. This is the first report of EGFR-mutated PDAC developing T790M-mediated resistance to a first-generation tyrosine kinase inhibitor (TKI). The course described here supports the conclusions that activating EGFR mutations in PDAC respond to EGFR TKIs, and resistance to therapy may be due to similar mechanisms to those seen in non–small cell lung cancer (NSCLC).
The genomic landscape of PDAC is dominated by recurring oncogenic lesions in KRAS, p53, CDKN2A, and SMAD4.5 Among these 4 well-known cancer genes, activating mutations in KRAS are nearly ubiquitous and present in >90% of cases.5 Numerous other genes are mutated or amplified in PDAC, but most of these occur at low allelic fractions, reflecting marked intratumoral heterogeneity and a complex mutational landscape.5 Although EGFR has been suggested to play a role in the pathogenesis of PDAC, because it is frequently overexpressed and may be associated with a poor prognosis, the presence of activating mutations in EGFR are notably rare.6–9
EGFR overexpression in PDAC provided the rationale for evaluating erlotinib in this disease. In a large randomized phase III trial comparing gemcitabine monotherapy with gemcitabine plus erlotinib, there was a survival benefit of just 10 days with the combination.6 Although the benefit with the addition of erlotinib achieved statistical significance (P=.038), the clinical impact of erlotinib in advanced PDAC is widely regarded as negligible.6 Given the high frequency of mutated KRAS, which predicts resistance to EGFR-directed therapies, and the low frequency of activating mutations in EGFR, the limited efficacy of erlotinib in this unselected population of patients with PDAC is expected.
Our patient's tumor was characterized by the unusual combination of a wild-type KRAS gene with an activating EGFR mutation. The mutation in this case is a deletion in exon 19, which encodes the kinase domain of the receptor. Deletions in exon 19 of EGFR are well described and represent approximately 40% of activating EGFR mutations seen in lung adenocarcinoma, in which they confer sensitivity to TKIs.10 Based on these genomic results, this patient was treated with erlotinib monotherapy. Remarkably, he had a partial and sustained response to erlotinib lasting for 280 days, which is comparable to EGFR-mutant lung cancer, wherein median progression-free survival (PFS) with TKIs is approximately 285 days.10 The durability of this patient's response to erlotinib after 2 lines of chemotherapy compares favorably with the PFS reported for the recently approved second-line therapy with 5FU/liposomal irinotecan (95 days) and for first-line therapies with FOLFIRINOX, gemcitabine/nab-paclitaxel, and gemcitabine/erlotinib (192, 165, and 115 days, respectively).2,3,6,11
Activating mutations in EGFR are most common in NSCLC. When the mutation is present in exon 19 or 21, which represents >96% of EGFR mutations, the response rate to EGFR TKIs exceeds 70%.10 Outside of NSCLC, EGFR mutations in exons 19 through 21 are rare, but have been described in cancers of the pancreas, head and neck, esophagus, biliary tract, prostate, colon, and ovaries, as well as in sarcomas and papillary renal cell carcinoma.12–18 Mutations in EGFR are present in rare cases of patients with PDAC, with The Cancer Genome Atlas (TCGA) database reporting EGFR mutations in 1 of 149 tumors (0.7%) and the COSMIC database reporting EGFR mutations in 6 of 1,599 (0.37%) PDACs.7–9,14,19,20 In contrast, Wang et al21 reported EGFR mutations in 49 of 88 (56%) unselected Taiwanese patients with metastatic PDAC; this result conflicts with the low prevalence reported in the TCGA and COSMIC databases and needs further validation. The presence of actionable mutations in EGFR outside of lung cancer has typically been detected by retrospective analysis. A review of the literature for actionable EGFR mutations in non-lung tumor types treated with EGFR-directed therapies is outlined in Table 1 (with the exception of Wang et al).14,15,17,18,22 Table 1 includes 2 cases of PDAC, which were retrospectively analyzed based on disease stabilization for >100 days on a phase II study of capecitabine plus erlotinib.14 Notably, in our case, a PR was achieved with erlotinib monotherapy. These reports and our experience both support the use of EGFR TKIs for non-lung cancers with actionable EGFR mutations.
The mechanism for acquired resistance to EGFR TKIs is well established in lung cancer and most commonly involves either development of the T790M mutation or MET amplification.23,24 The T790M mutation is methionine substitution for threonine at position 790 and is present in >60% of NSCLC cases that develop EGFR TKI resistance.25 Osimertinib is a third-generation irreversible TKI that has been approved for T790M-mutant NSCLC.23 The response we observed to erlotinib was initially substantial, with a 2-log reduction in CA 19-9 level and radiographic PR. However, the development of the T790M mutation ultimately prevented a durable response beyond 280 days. Unfortunately, our patient did not experience a response to osimertinib.
The initial biopsy had an exon 19 deletion in EGFR with an MAF of 16%, which, when accounting for both alleles, is assumed to be present in 32% of the sample. The sample was estimated to be <40% tumor and thus the exon 19 deletion was present in nearly all tumor cells. The T790M mutation was initially detected by TaqMan assay, and the MAF cannot be reported by this assay. However, retrospective pyrosequencing by the Yale Clinical Molecular Pathology Laboratory detected an MAF of 27% for T790M, with the sample estimated to be 90% tumor. In contrast to the exon 19 deletion, when accounting for both alleles, T790M would be expected to be present in 49% of tumor cells. In NSCLC, even T790M allelic fractions of <5% have been associated with resistance to first-generation TKIs.26
In T790M-mutated NSCLC, the overall response rate with osimertinib is reported to be 61%, with a disease control rate of 95%.23 The C797S mutation is the most common mechanism of acquired resistance to third-generation TKIs. However, it is unlikely to play a role in our patient who had primary resistance to osimertinib.27 For T790M-mutated
Literature Review of Nonlung Tumors With Activating Mutations in EGFR That Have Received Treatment With EGFR TKIs
Widespread use of precision medicine in PDAC has been constrained for many reasons, including insufficient tumor in available biospecimens, low incidence of actionable genomic lesions, and rapid clinical decline after standard chemotherapy. Despite these challenges, recent experience has shown that genomic analysis is feasible in most patients with PDAC and can identify actionable mutations.4 Our patient's clinical course highlights the potential clinical benefit of a biomarker-driven targeted therapy in refractory advanced PDAC. Additionally, our analysis supports the observation that, when mutated, the EGFR pathway functions similarly across tumor types with conserved mechanisms of resistance. Mutations in EGFR remain rare in PDAC, and the mutational landscape is predominantly highlighted by mutations for which targeted therapies are unavailable. However, given the limited treatment options for metastatic PDAC, genomic analysis should be considered for all patients with advanced disease.
Conclusions
In advanced PDAC, treatment options remain extremely limited after first-line chemotherapies are exhausted. This case illustrates the value and potential benefit of a precision medicine strategy. Actionable mutations in EGFR can be effectively targeted in PDAC, and appear to follow similar resistance patterns already established in NSCLC.
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