Seminars in Oncology
Volume 32, Issue 3 , Pages 329-335, June 2005

Redefining Bronchioloalveolar Carcinoma

  • Janessa J. Laskin

      Affiliations

    • Department of Medicine, Division of Medical Oncology, University of British Columbia, BC Cancer Agency, Vancouver, BC, Canada
    • Corresponding Author InformationAddress reprint requests to Janessa Laskin, MD, Division of Medical Oncology, BC Cancer Agency, 600 W 10th Ave, Vancouver, BC, V5Z 4E6 Canada
    • ,
  • Alan B. Sandler

      Affiliations

    • Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN
    • ,
  • David H. Johnson

      Affiliations

    • Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN

Article Outline

Bronchioloalveolar carcinoma (BAC) is a subtype of non-small cell lung cancer (NSCLC) with distinct clinical and pathologic features. Although BAC appears to be on a pathologic continuum with adenocarcinoma, the most recent World Health Organization (WHO) classification system has set stringent criteria for the diagnosis. Though malignant, these cancers tend to be peripheral and grow in a lepedic fashion along the alveolar septae without parenchymal invasion. This clear distinction based on histopathology allows for a more definite separation of the natural history and behavior of BAC in clinical studies. Recent clinical trials of molecular targeted anticancer therapies have led to a deeper understanding of the unique features of this cancer and suggest that BAC may require a different therapeutic paradigm from other NSCLCs.

 

Lung cancer is a common and deadly disease. At present, somewhat simplistic methods are used to make treatment decisions within the confines of the limited anticancer modalities available for lung cancers. In general, lung cancers are divided into small cell versus non-small cell carcinomas because enhanced radiation and chemosensitivity of small cell lung cancer mandates a nonsurgical treatment approach. Using this histopathologic distinction, approximately 85% of cancers are non-small cell cancers (NSCLCs), which can be further subcategorized by immunohistochemical markers.1 This heterogenous grouping includes bronchioloalveolar carcinoma (BAC). For the most part, the treatment of NSCLC is not differentiated by histologic category because until recently there have been few data to suggest that this would be of any benefit.

Novel anticancer treatment strategies have attempted to exploit our increasing knowledge of cancer biology, and molecularly targeted cancer therapies have come into clinical use in the last few years. BAC appears to preferentially respond to one of these classes of agents, the small molecules that inhibit the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). The observation of an improved response to EGFR tyrosine kinase inhibitors (TKI) has led to a resurgence of interest in this relatively uncommon subcategory of NSCLC and to a number of retrospective and prospective studies specifically in patients with BAC. The concept is even more significant since it is the first indication that a subtype of NSCLC may need to be treated as a distinct lung cancer entity and may lead the way into a new era of molecularly directed cancer therapy.

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Histology 

Although it was identified prior to 1960, it was at that time that Liebow coined the term “bronchioloalveolar carcinoma” to describe a peripheral, well-differentiated adenocarcinoma that did not distort the pulmonary interstitium.2 The critical elements of his description remain the basis for the more modern description of BAC, most recently updated in 1999 by the World Health Organization (WHO).3 These strict diagnostic criteria for BAC include lung cancers that are diagnosed in the absence of another primary adenocarcinoma, have no central bronchogenic source, are peripheral in location, have an intact pulmonary interstitium, and exhibit malignant cells growing along the alveolar septae.

This WHO histologic classification system is unambiguous and will serve to better isolate BAC from other lung cancers; however, it does have some practical limitations. First, patients with NSCLC frequently present with advanced or metastatic disease and thus a diagnosis of BAC might be based on a biopsy sample rather than a complete resection of a tumor. This leads to the second clinical issue: BAC shares many features with adenocarcinoma and often these two histologic patterns are seen together as if on a biologic continuum. Because of this association, other methods of subcategorization try to account for this relationship. Pure BAC that has no invasive elements represents approximately 3% to 4% of all lung cancers, whereas adenocarcinoma with some BAC features is far more common, as it includes cancers that are predominately BAC with only a small focus of invasive adenocarcinoma. The question is: What is the clinical relevance of this ratio of BAC to invasive adenocarcinoma? Ebright et al at Memorial Sloan-Kettering Cancer Center (MSKCC) addressed this issue in a retrospective review of 100 consecutive patients with surgically resected adenocarcinoma who exhibited varying degrees of BAC features.4 Tumors were reviewed and classified as pure BAC (PBAC, 47 patients), BAC with focal invasion (BWFI, 21 patients), and adenocarcinoma with BAC features (AWBF, 32 patients). Tumors categorized as BWFI consisted of tumor growth in a predominantly BAC pattern with an area of invasion comprising less that 10% of the total tumor mass. AWBF tumors consisted of invasive adenocarcinomas with a peripheral component growing along the bronchioles and alveolar septae in a typical BAC pattern (usually representing <15% of the mass). Although a clinical “pneumonic” pattern of disease and advanced stage were associated with a worse overall survival, there was no difference in survival based on the degree of invasion. Although there were no obvious differences in this study, the authors suggest that the current tumor-node-metastasis (TNM) staging and WHO histologic classification system do not adequately account for these partially invasive tumors and may need to evolve to include this mixed subset.

Terasaki et al have also examined the effect of varying degrees of invasive disease in a review of 441 patients treated between 1997 and 1999 at the National Cancer Hospital in Tokyo, Japan.5 The pathology from these tumors was reviewed and classified into three groups: BAC (by the 1999 WHO definition), adenocarcinoma with components of BAC and invasive cancer, and invasive adenocarcinoma without a BAC component. A comparison of the clinicopathologic features included tumor size, and expression of Ki67 (a marker of cellular proliferation), p53, and laminin-5 (a putative marker for tumor invasion). The adenocarcinoma with BAC group showed characteristics that were midway between the pure BAC and the adenocarcinoma-alone groups. The authors used the extent of local invasion to distinguish a mixed type of adenocarcinoma that could be regarded as early invasive cancer because of low rates of vascular, lymphatic, and pleural invasion, and no lymph nodal involvement.

This division between BAC and adenocarcinoma with BAC features is a relatively new concept and thus many of the reviews and descriptions of BAC prior to 1999 do not always make this distinction clear. Another way BAC has been described in the literature relates more to the putative cell of origin and gross appearance of the tumor; these are the subcategories of mucinous, nonmucinous, and sclerotic BAC. The mucinous form appears to arise from bronchial mucous cells, whereas the nonmucinous BAC tends to grow along the alveolar walls. Nonmucinous BAC arises predominantly from Clara cells or type II pneumocytes. Sclerotic BAC is similar in appearance to nonmucinous BAC but also contains an area of central sclerosis and may develop from pulmonary damage and scarring, or BAC itself may cause the scars to form. Although this is a useful descriptive tool, the relevance of this subtyping for clinical management is less obvious.

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Clinical Features 

The clinical features of BAC have primarily been described in retrospective reviews from single institutions and case series. The patterns of behavior associated with BAC are its tendency to present as multifocal disease with intrathoracic metastasis, slow rate of growth and progression, longer median survival, and increased prevalence in women and nonsmokers. These impressions have been cobbled together from several key institutional series to form the clinical gestalt of BAC held today. Some of these studies have focused more on specific features such as epidemiology, or etiology, and others provide a more general clinical picture.

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Epidemiology 

Many institutional series suggest that the incidence of BAC, along with adenocarcinoma, has been steadily increasing over the last few decades.4, 6, 7, 8, 9 For example, Barsky et al reviewed the cases of lung cancer treated at the University of California at Los Angeles (UCLA) between 1955 and 1990.7 Using standard diagnostic criteria of the time, 122 cases of BAC were identified from a total of 1,527 cases of lung cancer. Pathology specimens were reviewed for the published report and only a 5% discordance rate was identified between the original diagnosis and the diagnosis made with updated pathology criteria. Over this 35-year period the incidence of BAC rose from less than 5% to 24% (P <.001). A similar retrospective study of 505 cases of lung cancer diagnosed in New Jersey from 1973 to 1989 found that the incidence of BAC increased from 9.3% before 1978 to 20.3% from 1986–89.6 In contrast, a recent survey of the Surveillance, Epidemiology and End Results (SEER) database records from 1979 to 1998 did not detect an increase in the incidence of BAC over time.10 These investigators extracted data from a lung cancer cohort of 310,280 patients identifying 8,777 cases of BAC and 86,583 cases of adenocarcinoma. In this analysis the incidence of BAC remained stable at approximately 4%, whereas non-BAC adenocarcinomas steadily increased from 23% in 1979 to 32% in 1998. Unlike many of the smaller institutional series, a pathology review was not done on these SEER database cases. Thus, it is difficult to make a categorical statement regarding the true incidence of BAC since the diagnostic criteria have evolved over time; however, as the majority of these smaller trials retrospectively reviewed their cases and applied updated diagnostic criteria, the trend is likely a true phenomenon.7, 11

Unlike other NSCLCs, the male-to-female ratio in BAC is approximately equal. In the SEER database review (of >300,000 cases of lung cancer from 1979–98), the percentage of female cases was 54% in BAC, 44% in adenocarcinoma (non-BAC), 27% in squamous cell, 37% in large cell, 43% in small cell, and 40% in undifferentiated carcinomas.10 Among the 1,527 patients reviewed at UCLA, BAC accounted for 7.5% of the lung cancers in men compared to 25.6% of those in women.7 In other retrospective reviews this pattern has also been demonstrated, but the gender balance of BAC is usually compared to cases of adenocarcinoma and thus the trend may not seem as remarkable. For example, in a review of the 100 cases of surgically resected adenocarcinoma with BAC features from MSKCC between 1989 and 2000, 74% of the patients were female.4 Breathnach et al reviewed their institutional experience with patients with stage I BAC compared to stage I adenocarcinoma.12 Of the 138 patients identified between 1984 and 1992, 35 had BAC and 20 (61%) of these patients were female. The remaining 103 patients with adenocarcinoma 49 (47%) were female. This group of investigators also compared patients with stage IIIB/IV BAC to adenocarcinoma and again demonstrated a high percentage of women 48% (12 of 28) in the BAC group compared to 32% (40 of 124) in the adenocarcinoma group.13 The question of why this gender imbalance exists and whether it has any bearing on treatment response rates or survival remains unanswered.

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Etiology 

The relationship between smoking and BAC has been the subject of some debate. Institutional reviews suggest that a higher proportion of patients with BAC are never smokers relative to other NSCLC histologies. In the Breathnach series comparing BAC with adenocarcinomas, 33% (20 of 61) patients with BAC were nonsmokers compared to just 13% (29 of 229) of patients with adenocarcinoma.12, 13 In the UCLA study, of the 122 cases of BAC, 30% were never smokers, 30% smoked intermittently or remotely, and 40% were heavy smokers.7

Some of these data have been used to imply that BAC might not have a strong relationship to cigarette exposure; however, a case-control study suggests otherwise.14 In this retrospective study, 87 cases of BAC from 11 teaching hospitals in Long Island, Chicago, New York, and Philadelphia, diagnosed between 1977 and 1989, were reviewed for smoking history. In addition, 286 noncancer and 297 cancer patients were matched to cases for age, sex, race, hospital, and date of admission. Only 10% of male cases and 25% of female cases had never smoked. The relative risk of developing BAC was greater for subjects who started smoking at a younger age, smoked for a longer time, or smoked more cigarettes per day. Taking a slightly different approach, Brownson et al conducted a pathology review of cases of lung cancer diagnosed in nonsmoking women in Missouri from 1986 to 1991.15 Pathology slides were obtained for 482 cases (78% of those case identified from hospital records). Adenocarcinoma was the most common histologic type among former smokers and never-smokers. A total of 40 patients had BAC, 17 were lifelong nonsmokers, and two were former smokers. Collectively, these studies do implicate smoking as one possible etiologic factor in the development of BAC. However, smoking is not likely the only cause and may play more or less of a role in women.

The characteristic diffuse, multicenter presentation of BAC has led some investigators to postulate an infectious etiology for BAC, possibly a viral cause. This hypothesis is lent credence by a sheep model of this disease caused by an ovine retrovirus called Jaagsieke.16 Although, no cases of sheep-to-human viral transmission have been reported and the virus has never been isolated from human BAC tumor cells, it remains an interesting hypothetical model.17 A study from Taiwan has implicated subtypes of the human papillomavirus (HPV) as a potential causative factor for lung cancer in general, specifically for nonsmoking women.18 In this study, lung tissue from 141 patients with lung cancer and 60 noncancer control patients was examined for the prevalence of HPV 16/18 using nested polymerase chain reaction (PCR) and in situ hybridization. HPV was demonstrated in 55% of the lung cancer specimens compared to 27% of the noncancer control specimens (P = .0005). HPV was found only in the tumor tissue and not in the adjacent nontumor cells within the same patient. Notably, the odds ratio of HPV infection in nonsmoking women with lung cancer was much higher than in nonsmoking males with lung cancer (10.12 v 1.98). Adenocarcinomas had a higher prevalence of HPV positivity compared to squamous cell cancers. HPV 16 was detected in 43% versus 24% (P = .03) and HPV 18 was detected in 49% versus 29% (P = .027), in adenocarcinoma and squamous cell carcinomas, respectively. The authors concluded that these data suggest that HPV 16/18 infection is associated with lung cancer development in nonsmoking women. Although the data are provocative, the control group was small and the results of this study have not been replicated.

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Prognostic Factors 

The isolation of significant prognostic factors for BAC is hampered by the relative rarity of pure BAC, the mixture of BAC and adenocarcinoma in the literature, the evolution in the pathologic criteria for diagnosis, and the variability of treatment. Apart from the fact that advanced stage is generally associated with a worse prognosis, the management of patients with multiple nodules is somewhat controversial. For example, in a case series reported by Volpino et al that contained a subgroup of 34 patients with BAC, the multivariate analysis suggested that, although advanced stage was an adverse factor, the presence of multiple or satellite nodules was not an adverse prognostic factor.19 Thus the authors concluded that surgery should not be denied for patients with multiple nodules who are younger than 60 years of age and without lymph node involvement. Similarly, the Ebright series from MSKCC did not identify a survival difference between the unifocal and the multifocal pattern of disease.4 These trials support the general principle that, in the absence of mediastinal lymph node disease or distant metastasis, when possible multifocal BAC should be treated as separate primary tumors. In general, the extent of disease at diagnosis, resectability, and the presence or absence of symptoms appear to be the prognostic factors identified by the majority of institutional reviews of BAC.4, 19, 20, 21, 22

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Chemotherapy for BAC 

It is a common perception that BAC is less responsive to cytotoxic chemotherapy than other subtypes of NSCLC; however, there are very few studies that expressly examine this issue. Two older retrospective reviews comparing chemotherapy in BAC versus adenocarcinoma reported little difference in response rates or survival outcomes; however, both studies were limited by the older chemotherapy regimens used, an outdated pathology classification system, and small numbers of patients. Feldman et al reported a retrospective comparison of 25 patients with “metastatic” BAC and 223 with metastatic adenocarcinoma, all treated with cisplatin-based chemotherapy between 1975 and 1985.23 Clinical features were similar in both groups, except that more patients in the BAC group had previously undergone potentially curative surgical resections (44% v 9%). Multiple lung nodules were more common in the BAC group (72% v 29%; P = .003), whereas disseminated metastasis was more common in the adenocarcinoma group (60% v 39%; P = .04). Since this was an older study, the majority of patients received a regimen that included cisplatin and doxorubicin and more patients in the BAC group received a chemotherapy combination that included etoposide. There were no differences in response rates (32% v 33% for BAC and adenocarcinoma, respectively), times to progression (3 months for both), or durations of response (4 v 5 months for BAC and adenocarcinoma, respectively). Survival times were also similar with median survivals of 4 and 6 months and 2-year survival rates of 8% and 8.5% for BAC and adenocarcinoma, respectively. It should be noted that in comparison to recent clinical trials, these median survival times are short and likely relate to the chemotherapy regimens used at that time. Another series that focused on the prognostic implications of histopathologic subtyping of adenocarcinomas found that BAC had the longest median duration of response to chemotherapy.24 This study was a retrospective review and comparison of 259 consecutive patients with inoperable stage III adenocarcinoma. Unfortunately, only 13 patients (5%) had BAC (according to the 1981 WHO criteria) and therefore it is difficult to discern if the differences in response to chemotherapy is truly due to a biologic difference in response rate or tumor growth, or is merely a selection bias in a small group of patients. It also could be argued that the application of the more strict diagnostic criteria for BAC might cause a number of these cases in both studies to be reclassified as adenocarcinoma with BAC features and thus it is difficult to draw many conclusions regarding the putative chemosensitivity of BAC from these particular reviews.

The Southwest Oncology Group (SWOG) study S9714 was the first clinical trial to prospectively evaluate chemotherapy in BAC (Table 1). Fifty-eight patients with BAC received a 96-hour infusion of paclitaxel (35 mg/m2/d, repeated every 3 weeks).25 The majority of the patients were female (66%) and had stage IV disease (90%).The overall response rate was 14%, time to progression was 5 months, median survival was 12 months, and 3-year overall survival was 10%. The toxicity of the infusional paclitaxel dissuaded the general use of this regimen; nevertheless, this study provides a baseline for comparison of future BAC trials.

Table 1. Clinical Trials in BAC
StudyNo. of PatientsAgentResponse RateStable DiseaseMedian Survival (mo)
SWOG 97142558Paclitaxel14%NR12
SWOG 012638138Gefitinib
Chemo-naive21%30%12
Previously treated10%36%10
Miller et al4030Erlotinib27%NRNR

Abbreviation: NR, not reported.

All BAC chemotherapy studies are limited by their size and the use of older chemotherapy regimens; however, they do provide some information regarding the variability of chemo-responsiveness in this patient population. Despite the controversy regarding chemo-sensitivity, most oncologists offer patients with BAC the same chemotherapy options as patients with other types of NSCLC. Moreover, patients with BAC have not been routinely excluded from clinical trials of chemotherapy.

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Molecular Targeted Therapy 

Patients with advanced NSCLC of all histopathologic subtypes are commonly treated initially with a platinum-based doublet chemotherapy regimen. Chemotherapy typically effects a median survival of 8 to 10 months and 1-year survival rates of 30% to 40% in good performance status patients.26, 27, 28, 29 Although it is clear that chemotherapy is an appropriate treatment for many patients with lung cancer, there is a sense in which the benefits of traditional chemotherapeutic agents have reached a plateau.

In the past two decades our understanding of cancer biology has yielded insights into new therapeutic strategies. One potential approach is to interfere with the EGFR in order to disrupt intracellular signaling. EGFR is overexpressed in a variety of solid tumors and is particularly common in NSCLC with 40% to 80% of tumors expressing EGFR.30, 31, 32, 33 When stimulated, the transmembrane receptor triggers a cascade of intracellular signaling that affects cellular proliferation and apoptosis. Drugs targeting the EGFR include the TKIs, monoclonal antibodies, antisense oligonucleotides, and ligand-toxins or immunoconjugates. There are many compounds at various stages of clinical testing; however, gefitinib (ZD 1839, Iressa; AstraZeneca Pharmaceuticals, Macclesfield, UK) and erlotinib (OSI 774, Tarceva; OSI Pharmaceuticals/Genentech, San Francisco, CA; Roche Oncology, Basel, Switzerland) are furthest along in clinical trials and have provided the most information on the response of BAC to EGFR blockade.

Single-agent trials of gefitinib and erlotinib in patients with previously treated NSCLC have reported response rates of 9% to 39% and disease control rates (response plus stable disease) of 43% to 54% (Table 2).34, 35, 36 Importantly, two of the trials (with gefitinib) demonstrated that 34% to 43% of patients experienced an improvement in their tumor-related symptoms.34, 35 Based primarily on the results of the single agent trials, the US Food and Drug Administration approved the use of gefitinib for patients with NSCLC who have failed both a platinum- and a docetaxel-containing regimen.

Table 2. Clinical Trials of Single-Agent EGFR TKIs in NSCLC
Study and AgentDoseResponse RateStable DiseaseMedian Survival (mo)
IDEAL, 135 gefitinib250 mg/d v 500 mg/d18 v 19%36 v 51%7.6 v 8.0
IDEAL 2,34 gefitinib250 mg/d v 500 mg/d12 v 9%31 v 27%6.5 v 5.9
Perez-Soler et al,36/erlotinib (Tarceva)150 mg/d12%39%8.4

From the phase I and phase II trials of erlotinib and gefitinib there was an accumulation of anecdotal evidence suggesting that there was a subgroup of patients who responded more dramatically to these TKIs. Specifically, it was subjectively noted that women, nonsmokers, and patients with adenocarcinoma and BAC seemed to have a higher response rate. Important evidence to support this observation has come from single-institution retrospective analyses of patients treated with single-agent gefitinib. For example, a multivariate analysis identified the presence of any BAC features and being a never-smoker as being significantly correlated with response to gefitinib in a retrospective review of the 139 gefitinib-treated NSCLC patients treated at MSKCC.37

In light of these observations, two prospective phase II trials were undertaken in patients with BAC or adenocarcinoma with BAC features (Table 1). In a SWOG study, 138 such patients received single-agent gefitinib (102 chemotherapy-naive, 36 previously treated).38 The chemotherapy-naive group had a response rate of 21%, whereas the previously treated group had a response rate of 10%. The rates of stable disease were 30% and 36%, and the median survivals were 12 and 10 months for the previously untreated and treated groups, respectively. This median survivals were similar to that achieved with paclitaxel chemotherapy alone in the SWOG trial, but with less toxicity. In subgroup analyses, female gender, never-smokers, and the development of a rash to the gefitinib all predicted for an improved survival.

A similar study of erlotinib in 69 patients with BAC also found that smoking status and the presence of a rash predicted for response.39 In this series, the subclassification system developed at MSKCC (previously described) was used to distinguish pure BAC from adenocarcinoma with BAC features.4 This trial is continuing to enroll patients; however, preliminary data suggest that the results are at least comparable to the gefitinib data.40 Notably, patients with adenocarcinoma with BAC features were more likely to respond to erlotinib than patients with pure BAC (response rate of 30% v 7%). The reason for this difference and how the degree of invasion relates to response remain undefined.

These clinical trials and general observations have raised the question of whether patients who fit these specific criteria should be considered for first-line therapy with an EGFR TKI, particularly given that the response rates and median survival times are similar to that achieved with traditional chemotherapy but with less systemic toxicity. At present, this issue is highly controversial and requires further study before it could be recommended as standard of care.

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Future Directions 

Exciting reports from two institutions have identified somatic mutations in the tyrosine binding domain of the EGFR that appear to correlate with patients who have dramatic responses to gefitinib.41, 42 Both studies have generated preclinical in vitro models that lend biologic justification to this premise. Notably, the mutations appear to be most prevalent in patients who also fit the clinical parameters that “predict” response, that is, women, Southeast Asian origin, nonsmokers, and patients with adenocarcinoma or BAC.41 These studies involved a limited number of patients, but the results are intriguing and demand serious attention. The mutations appear to account for the minority of patients (∼10%) who have striking responses to the TKIs. However, it is highly likely that other mutations or gene modifications exist to explain the many other patients who benefit from minor responses or disease stabilization. A massive international effort is underway to replicate and expand on these results and to better define EGFR gene mutations.

A related area of investigation has focused on the interaction between the family of EGFR receptors and the downstream markers that might help explain or predict response to EGFR inhibition. It is interesting to note that the relative degree of EGFR over expression does not appear to correlate with a response to EGFR inhibitors.43, 44 In fact, squamous cell carcinomas exhibit the highest degree of EGFR positivity and yet seem to have the lowest response rate in clinical trials. Possible explanations for this apparent contradiction include the distinct possibility that the method of measuring EGFR expression does not represent the biologically active form of the receptor, coexpression of receptors is more important than EGFR expression alone, or that a high level of EGFR expression precludes the effectiveness of an agent that works by competitive inhibition. The seemingly conflicting information highlights the importance of designing trials with biologic correlates to help unravel the mystery of how these agents work in vivo.

One of these theories has been explored at the University of Colorado in studies that compared the EGFR-HER2 ratio for BAC, adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.45, 46, 47 It was noted that patients with BAC (n = 10) tended have a high level of EGFR-HER2 coexpression, whereas patients with squamous cell histology (n = 95) were more likely to overexpress EGFR, and patients with adenocarcinoma (n = 69) tended to overexpress HER2. A further study by these investigators demonstrated a significant correlation between nonmucinous BAC (n = 21) and EGFR expression, while mucinous BAC (n = 17) was more frequently related to HER2 overexpression. A similar experience was reported from a retrospective study of patients at the Vanderbilt Medical Center.48 Patients were identified (between 1990–2002) from the surgical database. The clinical charts and pathology were reviewed and the patients were reclassified into pure BAC (n = 26), adenocarcinoma with BAC features (n = 18), and adenocarcinoma (n = 14). A tissue microarray demonstrated a significant increase in the intensity of EGFR staining and Ki67, and a trend for increased HER2 intensity from BAC to adenocarcinoma. There were no differences in P-AKT levels across the three groups. HER2 expression correlated with EGFR (P = .002), and with Ki67 (P = .004). However, there was no significant correlation between EGFR or HER2 and any downstream markers of activity and there was no correlation between smoking and any marker. It is possible that the ratio of EGFR-HER2 expression may have a fundamental impact on tumor response, but these relationships are still under investigation.

It has been postulated that the patients who respond to EGFR TKIs have tumors that are more biologically dependent on EGFR activation for cell proliferation and anti-apoptosis. This idea has been explored by Cappuzzo et al, who looked at the Ras/raf/Map-K and the PI3K-AKT pathways to see if immunohistochemistry-positive tumors predicted for a response to gefitinib.49 One hundred six patients with advanced NSCLC from three Italian institutions were enrolled and treated with single-agent gefitinib until they developed progressive disease or intolerance. Tissue from the time of initial diagnosis was obtained for 103 patients and the P-AKT and P-MAPK status was determined by immunohistochemistry. P-AKT was positive in 51(50%) and P-MAPK was positive (2+/3+) in 23 (22%) and negative (0/1+) in 80 (78%). P-AKT positivity was significantly correlated with female gender, nonsmoking, and BAC histology. Compared to P-AKT-negative tumors, P-AKT-positive tumors had a higher response rate (26% v 4%; P = .003), disease control rate (61% v 24%; P < .001) and longer time to progression (5.5 v 2.8 months; P = .004). No differences were seen with P-MAPK staining positive or negative. Multivariate analysis identified P-AKT-positive status as a significant predictor of disease response to gefitinib.

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Summary 

Although BAC has been a discrete clinical entity for decades, it is only recently that we may have found cause to take advantage of this distinction. Because of the relative rarity of pure BAC, the majority of information has been collected from retrospective reviews and institutional series. It would appear that BAC frequently follows a more indolent clinical course, is more common in women, and may be less strongly associated with cigarette exposure. As studies of BAC progress and expand it might become clinically important to separate pure BAC from adenocarcinoma with and without BAC features.

In harmony with this observation is the recognition of a clustering of clinical features that predict for a response to gefitinib and erlotinib, and possibly other EGFR inhibitors as well. These clinical features include female gender, BAC or adenocarcinoma, possibly ethnic origin (Southeast Asian), and nonsmokers. Translational research has fostered the rapid exchange of information between the clinic and the basic scientists that develop and test new anticancer agents. These kinds of exchanges have led to the description of a number of molecular features that may be predictive of response, such as tumor is with P-AKT positivity, and those with a mutation in the adenosine triphosphate binding domain of the tyrosine kinase. Collectively, these bits of information and the undefined relationship between these pieces of the clinical puzzle have sparked a flurry of exciting translational research activity that will likely change our perception of lung cancer treatment forever.

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PII: S0093-7754(05)00083-7

doi:10.1053/j.seminoncol.2005.02.013

Seminars in Oncology
Volume 32, Issue 3 , Pages 329-335, June 2005

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