Patients with EGFR-mutant lung cancer have a prolonged survival compared to the median survival of 12 months commonly reported for patients with advanced NSCLC.(29
) While this may in part be due to durable responses to EGFR TKIs, it also is likely that these cancers have a distinct biology from that of EGFR wild-type lung cancers, with greater chemo-sensitivity and better surgical outcomes (3
). However, this remains a heterogeneous population: some patients with EGFR-mutant lung cancer do poorly after an initial response to TKI while others can live for many years despite advanced disease. Our data suggest that detection of the T790M mutation after progression on TKI identifies a subset of EGFR-mutant lung cancer with a distinct natural history and longer survival, which is consistent with preclinical data showing that EGFR-mutant cell lines that acquire the T790M mutation display indolent growth (20
). If verified prospectively, the T790M mutation would be one of the first acquired
molecular biomarkers with prognostic value in solid tumor oncology.
Our data suggest that patients with and without T790M after progression on TKI have very different clinical features of progression, likely driven by their different genotypes. The absence of T790M after progression, likely indicating some “other” resistance mechanism, is associated with earlier development of new metastatic sites of disease and a poorer performance status, contributing to the shorter survival of these patients. Alternatively, T790M-mediated resistance is more likely to occur in an existing site of disease, and has also been found to be associated with indolent disease growth (J. Chmielecki, et al, submitted)(20
), characteristics that may explain the longer survival of these patients. Importantly, the vast majority of patients in our dataset were maintained on chronic EGFR TKI therapy after developing resistance in order to prevent growth of TKI-sensitive clones, in addition to subsequent cytotoxic therapies intended to treat the subset of resistant clones (9
). While this is not standard practice at most institutions, we believe this strategy may help maintain the indolent characteristics of T790M-associated progression, though it may make our findings difficult to replicate with patient cohorts in which TKI was routinely discontinued upon progression.
The existence of two biologic subtypes of acquired resistance has important implications for clinical trials performed in this setting (9
), as these two populations likely require distinct treatment approaches. For example, T790M positive patients may be more likely to maintain dependence on the EGFR signaling axis,(31
) and thus may benefit from newer strategies targeting EGFR and its signaling pathway (32
). This possible role for T790M at resistance as a predictive or prognostic biomarker is complicated by the need for re-biopsy to obtain tumor DNA, a strategy which can be logistically challenging, though we and others have found it feasible (21
). Technologies allowing minimally invasive determination of T790M status from peripheral blood specimens or cytologic specimens are in development and may simplify this process (18
For patients without T790M, given their poorer prognosis, it is extremely important that we develop a better understanding of the molecular mechanisms of TKI resistance. MET amplification has been identified as one alternate mechanism of acquired resistance (24
), however in the subset of our cohort tested by FISH the prevalence was only 11% (with a single case of high level amplification). Alternate pathways of TKI resistance, of which several have been hypothesized (39
), are actively being investigated by multiple groups using high throughput mutation testing, siRNA screens, and gene expression microarray analysis.
The positive prognostic implications of T790M in the acquired resistance setting differ from its negative prognostic role prior to treatment with TKI.(18
). In pretreatment EGFR mutant lung cancers, the reported prevalence of “de novo” T790M has varied widely (1% to 38%)(3
), with the upper end of this range possibly reflecting false positive results with some T790M assays.‡
In the pretreatment setting, patients with no T790M detected would be expected to do better because they harbor only a sensitizing mutation and have not yet acquired a resistance mutation (16
). In contrast, patients who are “T790M negative” in the resistant setting must harbor some other mechanism of resistance, leading to their poorer prognosis. Note that in our analysis we included only patients who demonstrated a clinical benefit on TKI, therefore patients with a preexisting de novo T790M mutation and disease refractory to TKI treatment would not be included in our cohort. Analysis is ongoing to determine whether patients harboring the T790M after acquired resistance additionally harbor low levels pretreatment; however, no such cases have yet been identified in our cohort (M. E. Arcila, et al, submitted)(42
One possible limitation of our data is that only a subset of all EGFR-mutant lung cancer patients had biopsy tissue available for molecular analysis after progression on TKI, leading to the exclusion of patients without adequate biopsies. One could hypothesize that poor-prognosis patients would be unable to undergo re-biopsy and would be left out of our analysis, skewing our results. For example, only 25% of our cohort harbored EGFR exon 21 mutations, rather than the expected 40% (1
), and these types of mutations have previously been found to be associated with poorer outcomes (2
). However, when we compared our cohort to a reference cohort of all EGFR-mutant lung cancer patients treated at the institution we found no difference in median survival from date of advanced disease (Supplementary Figure 1
). We therefore believe that our sample accurately represents patients with EGFR-mutant lung cancer treated with erlotinib or gefitinib.
Because of the unique patient population analyzed in this study, accrual and analysis occurred over several years during which time molecular testing techniques have evolved. Initial testing techniques employing direct sequencing and fragment analysis detect mutant clones when present in at least 10–20% of DNA studied. With these techniques, false negative results can occur when specimens contain significant amounts of stromal or inflammatory tissue. Our current testing mechanism, using direct sequencing augmented by a locked nucleic acid (LNA) which inhibits wild-type DNA amplification, is able to detect T790M when present in as little as 0.1% of DNA studied, significantly improving sensitivity of testing (M. E. Arcila, et al, submitted)(23
). This may explain why we have found a somewhat higher prevalence of T790M than has previously been reported (12
In conclusion, we find that patients with acquired resistance to gefitinib and erlotinib harboring the T790M mutation have a distinct natural history, and that this mutation identifies a distinct subset of patients with a longer survival after progression and later development of new metastases. Our data suggest that knowledge of T790M status is important for the clinical care of these patients as well as for the optimal design and interpretation of clinical trials in this setting. A better understanding of the biologic mechanisms of non-T790M-mediated acquired resistance is needed to develop treatments for this poorer prognosis population.
This analysis evaluates whether there is prognostic significance to the T790M mutation in patients with EGFR mutant lung cancer who have developed acquired resistance EGFR tyrosine kinase inhibitors (TKIs) like erlotinib. Preclinical data have suggested that T790M mutant cell lines have indolent growth, but such an indolent behavior has not been previously demonstrated clinically. In this analysis, we find that patients with T790M-mediated acquired resistance have relatively favorable progression characteristics and clinical outcomes, suggesting that this mutation identifies a subset of cancers with a distinct biology. Our findings indicate that T790M may be an important prognostic and mechanistic biomarker in patients with acquired resistance, and mutation status should be routinely determined in patients enrolling in clinical trials for acquired resistance.