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Clinical Cancer Research Vol. 10, 4205S-4209S, June 15, 2004
© 2004 American Association for Cancer Research

Proceedings of the First International Conference

Bronchioloalveolar Carcinoma

A Model for Investigating the Biology of Epidermal Growth Factor Receptor Inhibition

David R. Gandara1,4, Howard West2,4, Kari Chansky4,5, Angela M. Davies1,4, Derick H. M. Lau1,4, John Crowley4,5, Paul H. Gumerlock1,4, Fred R. Hirsch3,4 and Wilbur A. Franklin3,4

1 University of California Davis Cancer Center, Sacramento, California; 2 Swedish Tumor Institute, Seattle, Washington; 3 University of Colorado Cancer Center; 4 Southwest Oncology Group, San Antonio, Texas; 5 Southwest Oncology Group Statistical Office, Seattle, Washington


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 DISCUSSION
 OPEN DISCUSSION
 REFERENCES
 
Bronchioloalveolar carcinoma (BAC) is a previously uncommon subset of non-small cell lung cancer (NSCLC) with unique epidemiology, pathology, clinical features, radiographic presentation, and natural history compared with other NSCLC subtypes. Recent data suggest that the incidence of BAC is increasing, notably in younger nonsmoking women. Despite reports of prolonged survival after repeated surgical resection of multifocal lesions and slow growth kinetics, advanced bilateral or recurrent diffuse BAC remains incurable, with the vast majority of patients dying of respiratory failure or intercurrent pneumonia within 5 years. Limited data suggest that chemotherapy may yield poor results in BAC. However, anecdotal reports of prolonged complete response to tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR), a member of the human epidermal growth factor receptor (erbB) family, have raised considerable interest in studying this NSCLC subset. Here we present clinical data and preliminary results of correlative science studies analyzing human epidermal growth factor receptor pathways from the following two prospective Southwest Oncology Group clinical trials performed in advanced stage BAC: S9714 testing a 96-h continuous infusion of paclitaxel (Taxol) and S0126 evaluating the small molecule EGFR inhibitor gefitinib (ZD1839 or Iressa). These studies provide a biological rationale for investigating BAC as a model of predictive markers of EGFR inhibition.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
DISCUSSION
 OPEN DISCUSSION
 REFERENCES
 
Bronchioloalveolar carcinoma (BAC) is a pathological subtype of non-small cell lung cancer (NSCLC) that appears to be steadily increasing in incidence. In one report, BAC rose 4-fold over the period between 1955 and 1990 (1) . Compared with other subtypes of NSCLC, BAC is characterized by a distinct clinical presentation, radiographic appearance, and natural history (2) . Further distinguishing BAC from other types of NSCLC is a higher percentage of women, a younger age distribution, and a higher incidence in nonsmokers (2) . These differences raise the question of whether BAC represents a separate entity with an epidemiology distinct from that of other NSCLCs. In support of this concept are marked similarities between BAC and ovine pulmonary adenomatosis in sheep, caused by the Jaagsiekte retrovirus (3) . The impact of various histological subsets of BAC (pure BAC, BAC with invasion, and adenocarcinoma with BAC features) on the course of the disease also remain controversial (4) .

Although patients may be cured after surgical resection of focal BAC, there is no optimal established therapy for multilobar or recurrent disease. Because of the relative infrequency of this malignancy in the past, reports of BAC in the literature have generally been restricted to retrospective reviews of a single institution’s experiences in limited numbers of patients. BAC patients are often excluded from NSCLC clinical trials, attributable in part to the difficulty in measuring objective response of diffuse infiltrative lesions. Further distinguishing BAC is the general perception that chemotherapy is less effective in BAC than in other NSCLC subtypes. For all these reasons, prospective clinical trials directed toward the therapy of BAC are warranted.

Although over one-half of NSCLC specimens express epidermal growth factor receptor (EGFR), only 10–20% of patients achieve an objective response when treated with EGFR tyrosine kinase inhibitors (TKIs) (5 , 6) . Furthermore, although EGFR has been reported to confer a poor prognosis in surgically resected NSCLC, initial correlative studies suggest that the level of EGFR protein expression as assessed by immunohistochemistry (IHC) has poor predictive value for response to EGFR TKIs (7, 8, 9) . We and others have shown that NSCLC of squamous cell histology most often expresses high levels of EGFR protein (10) . Paradoxically, it may be the least responsive clinically to EGFR blockade (5) . Furthermore, in a few BAC patient tumor specimens, we found relatively high co-expression of EGFR and human epidermal growth factor receptor 2 (HER2), distinguishing this subtype from others, including other adenocarcinomas (Fig. 1Citation ; Ref. 10 ). These data and anecdotal reports of complete response of BAC to EGFR TKIs led us to examine tumor specimens from our prior Southwest Oncology Group BAC study (S9714) for EGFR/HER signal transduction pathways and to perform a prospective clinical and correlative science trial (S0126) evaluating gefitinib in patients with advanced BAC. We hypothesized that BAC represented a unique model for the study of predictive markers of EGFR blockade and that results in BAC would provide insight into optimizing EGFR inhibitor therapy in other forms of NSCLC as well as in other tumor types.



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  		Fig. 1. Immunohistochemistry scores for epidermal growth factor receptor ( , score >200) and human epidermal growth factor receptor 2 ( , score >50) by histological subtype of non-small cell lung carcinoma.

 
Clinical Trials in Advanced Stage BAC.
S9714 was the first prospective clinical trial to evaluate therapy of BAC. On the basis of preclinical data supporting continuous exposure to paclitaxel and Southwest Oncology Group investigator-related experience in BAC using this dose schedule, 58 chemo-naive patients with advanced stage BAC underwent treatment with a 96-h infusion of paclitaxel, 35 mg/m2/day, repeated every 3 weeks (11) . The majority of patients were female (66%) and all had stage IV (90%) or stage IIIB disease (10%). The response rate was 14%, time to progression was 5 months, and median survival was 12 months. Despite this relatively long median survival time, at 3 years of follow-up only 10% of patients remained alive (11) . Toxicity from 96-h infusion paclitaxel was substantial, dampening enthusiasm for this therapeutic approach. Nevertheless, this trial provides a unique historical control for patient demographics and chemotherapy results in advanced stage BAC. In addition, tumor specimens from this trial provided us with a pathological database for molecular analysis of HER family pathways in BAC, absent the influence of EGFR inhibitor therapy. Specimens were scored from 0 to 400 by quantitative IHC, based on the intensity of staining (0 to 4+) multiplied by the percentage of cells staining, as described previously (10) . By Pearson correlations, HER2 levels were positively associated with the downstream marker phosphorylated mitogen-activated protein kinase (pMAPK, aka extracellular signal-regulated kinase 1/2), for both nuclear (n) and cytoplasmic (c) staining, P < 0.01, whereas there was no correlation of EGFR with either HER2 or pMAPK (11) . These data suggest that HER2 may be particularly important in driving signal transduction in BAC and that therapeutic trials of EGFR inhibitors should take HER2 and downstream pathways such as MAPK into account as possible predictive markers of sensitivity or resistance.

In the follow-up trial S0126, which completed patient accrual in June of 2003, 139 patients (102 chemo-naive and 37 chemotherapy-pretreated) with advanced stage BAC were treated with gefitinib at a starting dose of 500 mg/day. Patient characteristics were similar to those in the predecessor study S9714. Because response is often difficult to quantitate in BAC because of the diffuse infiltrative nature of lesions, both response evaluation criteria in solid tumors (RECIST) and a novel computer-assisted image analysis (CAIA) methodology were used. Indeed, 40% of patients had only diffuse infiltrates, whereas an additional 32% had a combination of diffuse infiltrates plus mass lesions. In a preliminary analysis, the response rate is 19% in chemo-naive patients and 12% in chemotherapy-pretreated patients by response evaluation criteria in solid tumors, whereas the overall response rate by CAIA is 22% (12) . The sole clinical parameter predictive of survival was female sex (P = 0.007) (13) . As in our previous correlative studies, baseline tumor specimens were analyzed by quantitative IHC for total EGFR, HER2, and the downstream markers pMAPK and pAkt, among others. Pearson correlations (Table 1)Citation demonstrated similar findings to those of S9714. Although EGFR levels did not correlate with pMAPK, there was a strong statistical correlation of pMAPK with HER2 (P = 0.001). Of interest, neither EGFR nor HER2 levels correlated with pAkt (nuclear or cytoplasmic).


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  		Table 1 Pearson correlations for molecular markers in S0126

p-MAPK correlates with HER2, not EGFR.

 
These potential predictive markers were then assessed for an impact on survival. This report describes findings in chemo-naive patients from the S0126 study, the subgroup with sufficient follow-up time for analysis at this time. Analysis of currently available specimens shows no statistical correlation of survival with EGFR or HER2 as single markers. However, low levels of pMAPKn and pMAPKc (P = 0.03 and 0.009, respectively) correlate positively with longer survival (Fig. 2, A and B)Citation . Neither of these markers correlated with survival in the predecessor trial S9714, in which patients received paclitaxel (data not shown). Taken together, these findings suggest that MAPK is not merely prognostic in this setting but rather represents a predictive marker for survival after treatment with gefitinib. Furthermore, as shown in Fig. 3Citation , a combination index of low levels of both HER2 and pMAPKn is highly predictive of prolonged survival under the influence of gefitinib (P = 0.008). Conversely, expression levels of pAkt were not predictive of survival (P = 0.74).



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  		Fig. 2. A, survival by pMAPKn (high ≥100, low <100). B, survival by pMAPKc (high, ≥100; low, <100). pMAPK, phosphorylated mitogen-activated protein kinase; n, nuclear; c, cytoplasmic.

 


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  		Fig. 3. Survival by combination index of HER2 and pMAPKn (high, HER2 ≥ 150 or pMAPKn ≥ 100; low, HER2 < 150 and pMAPKn < 100). HER2, human epidermal growth factor receptor 2; pMAPK, phosphorylated mitogen-activated protein kinase; n, nuclear.

 
Correlations of markers with tumor response by response evaluation criteria in solid tumors and CAIA in S0126 have not yet been completed. However, preliminary data are available regarding 39 patients for whom CAIA response has been matched with marker status in a blinded fashion. Only 2 of 14 patients with high pMAPKn have complete or partial response by CAIA. Conversely, 8 of 25 patients with low pMAPKn are responders by CAIA. These differences do not reach statistical significance but are provocative considering the survival data described above. Analysis of additional cases is ongoing and should shed further light on the predictive value of high pMAPK for lack of response to gefitinib.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 DISCUSSION
OPEN DISCUSSION
 REFERENCES
 
Conceptually, the dual roles of EGFR in cellular proliferation (through Ras-Raf-MAPK pathways) and resistance to apoptosis [phosphatidylinositol 3-kinase (PI3K)-Akt pathways] make it an attractive target for development of cancer therapeutics (Fig. 4)Citation . Moreover, EGFR is highly expressed in a majority of solid tumors including NSCLC. Despite high expectations based on these biological observations and preclinical data suggesting wide applicability, selective EGFR TKIs have shown limited clinical efficacy. Only 10–20% of NSCLC patients treated with gefitinib or erlotinib (OSI774, Tarceva) demonstrate objective response. Most importantly, however, initial reports suggest that the level of protein expression of the presumed target is not predictive of benefit (9) . In fact, those NSCLC patients with squamous cell histology, who have the greatest frequency of high level EGFR expression, may be least likely to respond to EGFR TKIs. These data, which are in stark contrast to the high predictive value of HER2 expression for efficacy of trastuzumab (Herceptin), whether assessed by IHC or fluorescent in situ hybridization, have led to considerable debate about whether a reliable molecular marker(s) predictive of therapeutic benefit from EGFR inhibitors will be identified. Instead, at present, clinical pathological features such as female sex, nonsmoking status, and adenocarcinoma or BAC histology appear to best define those patients likely to respond (5) . Because BAC is a biological variant of adenocarcinoma and is characterized by a higher ratio of females and nonsmokers when compared with other NSCLC subtypes, it follows that patients with BAC may be an ideal population in which to test EGFR inhibitor therapy. Indeed, our results with gefitinib in BAC are similar to those recently reported using the EGFR tyrosine kinase inhibitor erlotinib in 50 patients with advanced stage BAC (14) . In that study, the response rate was 23%, with women and never-smokers having a higher chance of response (14) .



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  		Fig. 4. Dual roles of epidermal growth factor receptor (EGFR) in proliferation and antiapoptotic pathways. MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; PI3K, phosphatidylinositol 3'-kinase; NF{kappa}B, nuclear factor {kappa}B; I{kappa}B, inhibitor of nuclear factor-{kappa}B.

 
We have demonstrated previously that by comparison with other histological subtypes of NSCLC, BAC specimens show co-expression of EGFR and HER2 (10) . Of all possible combinations for HER family dimerization after ligand binding, HER2 is reported to be the preferred dimerization partner, and the EGFR/HER2 heterodimer appears to be most important for proliferative signaling (15 , 16) . Thus, co-expression of EGFR and HER2 in BAC patients would theoretically make them susceptible to disruption of this pathway. In our S9714 and S0126 studies, quantitative IHC was consistent in demonstrating that protein expression levels of the Ras-Raf downstream marker pMAPK correlated with HER2 expression, not EGFR. There was no correlation of either EGFR or HER2 with pAkt.

Furthermore, neither EGFR nor HER2 expression alone, nor a combination of the two, predicted for survival with gefitinib therapy in S0126. Instead, high levels of pMAPK, either nuclear or cytoplasmic, were the only single parameters predictive of poor survival. Why high levels of activated MAPK are associated with reduced survival in S0126 remains unclear, but this question leads to a logical series of possible explanations. Because MAPK plays a central role in proliferative signaling through the Ras-Raf-MEK pathway, high constitutive expression may reflect mutation of upstream oncogenes such as Ras, an event known to occur in over 30% of adenocarcinomas of the lung (17 , 18) . Analysis of S0126 specimens for Ras mutations is under way. It is of interest that expression levels of Akt did not predict survival with gefitinib therapy in our trial. High Akt levels have been implicated as a resistance marker for gefitinib (19) .

In summary, our studies confirm that the unique molecular profile of HER family pathways in BAC make it a good model for the study of EGFR inhibitors. Our ongoing studies in BAC and other histological subtypes of NSCLC will assist in validating the results described here and in determining whether our findings regarding predictive markers are generalizable to other clinical settings and other EGFR inhibitors, including monoclonal antibody therapy. These studies incorporate more extensive testing of HER family pathways, including determination of mRNA expression levels from baseline tumor tissue, gene copy number by fluorescent in situ hybridization, mutational status, and testing for genomic polymorphisms. Where appropriate, results will be compared with quantitative IHC as described here. Although we acknowledge the potential limitations of IHC, the general applicability of this methodology for widespread use makes it appealing if it proves to be of reliable predictive value. Additional study of BAC is indicated to provide further insight into the underlying biology of EGFR pathways and into the predictive markers of clinical benefit to EGFR inhibition. On the basis of the results of studies described here, we propose that future clinical trials in BAC investigate therapeutic strategies directed toward dual inhibition of EGFR and HER2.


   OPEN DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 DISCUSSION
 OPEN DISCUSSION
REFERENCES
 
Dr. Roy Herbst: Does this have to be BAC or do you think that you could look at the same predictive markers in patients with adenocarcinoma or squamous carcinoma who have responded to these agents?

Dr. Gandara: These are preliminary data, but nevertheless this may apply for non-small cell lung cancer and for some other tumor types as well. We are collecting tissue in several ongoing trials of EGFR inhibitors. We are also collecting genomic DNA from peripheral blood mononuclear cells, because we are interested in whether newly described EGFR polymorphisms correlate with outcome and whether also there may be racial differences in these polymorphisms that might explain differences in response or toxicity, for example, in Japanese patients.

Dr. Geoffrey Shapiro: Skin would obviously be an easier surrogate proliferating tissue to look at in large populations. Was skin analyzed and were there the same findings with MAP kinase and phosphorylated Akt in skin biopsies?

Dr. Gandara: We used buccal mucosa. We are having some problems with the assays because of bacterial contamination. We have demonstrated in normal buccal mucosa EGFR, phospho-EGFR, p27, and all the downstream markers, but it is a difficult analysis. We’re probably going to use hair follicles as a surrogate in our next study because it is hard to get serial skin biopsies in a cooperative group.

Dr. Bruce Johnson: One issue concerns the reproducibility of defining BAC. In your two trials, what happened when you went from the institution’s review to a central pathologic review? How many changed, and did it have any impact on the outcome?

Dr. Gandara: For the S9714, there were only three patients whom Wilbur Franklin, our central review pathologist, thought had no components of BAC; they were well-differentiated adenocarcinomas. For the S0126, there are 9 out of 142 that are in question. They are not ineligible, because we allowed institutional eligibility to put the patient on the trial. The data set that I showed you does not change whether they are included or excluded. The P values shift just a bit, but none shift from significant to insignificant or vice versa.

Dr. Thomas Lynch: You mentioned that MAP kinase correlated with HER2. Did it correlate with response?

Dr. Gandara: This response issue is very problematic for BAC, and even between our institutions and central review there is a lot of disagreement regarding these infiltrates. If they are less dense, do you call that a response? By RECIST [response evaluation criteria in solid tumors], you cannot. That is why I don’t want to overemphasize the response data and rather concentrate on the survival.

Dr. Lynch: Dr. Johnson, yesterday you said that you thought MAP kinase should be looked into more often as a predictive factor. What are your thoughts about these data?

Dr. Johnson: I personally believe it is the leading candidate. One of the other potential problems is how much of an effect phosphatases have on the phospho-specific antibodies. So, it would be very helpful if people who have laboratories take a look to see how long a nude mouse tumor can be left out on the bench and still have the phospho-specific antibodies detect the phosphorylated receptors. That would help tell us how long it can sit out before getting processed in the pathology department and still have the phosphorylated receptor detected.

Dr. Gandara: That’s the other reason I think having this historical database of the S9714 trial is useful, because you also don’t want to attribute something to treatment that is really only prognostic for that tumor. So the fact that the MAP kinase was not prognostic in the prior trial, but here in S0126, the survival clearly separates, was comforting to us that we are not just reinventing a prognostic variable.

Dr. Herbst: There are going to be differences between when you sample and how you measure. In prospective studies, I think we will need to have uniform methods, probably for collection and sampling of tissue before treatment.


   ACKNOWLEDGMENTS
 
We thank Chris Mahaffey for technical support in preparing this manuscript.


   FOOTNOTES
 
Presented at the First International Conference on Novel Agents in the Treatment of Lung Cancer, October 17–18, 2003, Cambridge, Massachusetts.

Grant support: Supported in part by NIH Grants CA38926, CA32102, N01-CM17101 and by the Hope Foundation.

Requests for reprints: David R. Gandara, University of California, Davis, UCD Cancer Center, 4501 x St, Sacramento, CA 95817-2229. Phone: (916) 734-3772; Fax: (916) 734-7946; E-mail: david.gandara{at}ucdmc.ucdavis.edu


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 DISCUSSION
 OPEN DISCUSSION
 REFERENCES
 

  1. Barsky SH, Cameron R, Osann KE, Tomita D, Holmes EC Rising incidence of bronchioloalveolar lung carcinoma and its unique clinicopathologic features. Cancer (Phila), 73: 1163-70, 1994.
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