HonCode

Go Back   HER2 Support Group Forums > Articles of Interest
Register Gallery FAQ Members List Calendar Search Today's Posts Mark Forums Read

Reply
 
Thread Tools Display Modes
Old 09-19-2013, 10:30 AM   #1
'lizbeth
Senior Member
 
'lizbeth's Avatar
 
Join Date: Apr 2008
Location: Sunny San Diego
Posts: 2,214
Post Targeted Vs Chemo - and targeted wins!

The Impact of Initial Gefitinib or Erlotinib versus Chemotherapy on Central Nervous System Progression in Advanced Non–Small Cell Lung Cancer with EGFR Mutations

Stephanie Heon,1,2,3 Beow Y. Yeap,2,4 Neal I. Lindeman,5,6 Victoria A. Joshi,5,6,7 Mohit Butaney,1 Gregory J. Britt,2,8 Daniel B. Costa,2,8 Michael S. Rabin,1,2,3 David M. Jackman,1,2,3 and Bruce E. Johnson1,2,3

Author information ► Copyright and License information ►

The publisher's final edited version of this article is available free at Clin Cancer Res
See other articles in PMC that cite the published article.


Go to:
Abstract

Purpose

This retrospective study was undertaken to investigate the impact of initial gefitinib or erlotinib (EGFR tyrosine kinase inhibitor, EGFR-TKI) versus chemotherapy on the risk of central nervous system (CNS) progression in advanced non–small cell lung cancer (NSCLC) with EGFR mutations.

Experimental Design

Patients with stage IV or relapsed NSCLC with a sensitizing EGFR mutation initially treated with gefitinib, erlotinib, or chemotherapy were identified. The cumulative risk of CNS progression was calculated using death as a competing risk.

Results

One hundred and fifty-five patients were eligible (EGFR-TKI: 101, chemotherapy: 54). Twenty-four patients (24%) in the EGFR-TKI group and 12 patients (22%) in the chemotherapy group had brain metastases at the time of diagnosis of advanced NSCLC (P = 1.000); 32 of the 36 received CNS therapy before initiating systemic treatment. Thirty-three patients (33%) in the EGFR-TKI group and 26 patients (48%) in the chemotherapy group developed CNS progression after a median follow-up of 25 months. The 6-, 12-, and 24-month cumulative risk of CNS progression was 1%, 6%, and 21% in the EGFR-TKI group compared with corresponding rates of 7%, 19%, and 32% in the chemotherapy group (P = 0.026). The HR of CNS progression for upfront EGFR-TKI versus chemotherapy was 0.56 [95% confidence interval (CI), 0.34–0.94].

Conclusions

Our data show lower rates of CNS progression in EGFR-mutant advanced NSCLC patients initially treated with an EGFR-TKI compared with upfront chemotherapy. If validated, our results suggest that gefitinib and erlotinib may have a role in the chemoprevention of CNS metastases from NSCLC.



Go to:
Introduction

The development of central nervous system (CNS) metastases is a common and serious complication in non–small cell lung cancer (NSCLC), with an adverse impact on quality of life and survival (1). Phase III trials of cytotoxic chemotherapy for stage IV NSCLC have commonly reported the frequency of brain metastases at the start of systemic therapy, but have seldom differentiated between CNS and non-CNS sites of disease progression during the trial (2, 3). Conversely, the incidence of brain metastases has been widely reported in studies of patients with locally advanced NSCLC treated with definitive locoregional therapies. The addition of chemotherapy to chest irradiation and/or surgical resection in patients with stage III NSCLC has reduced extracranial distant relapses, but has had a limited impact on the frequency of brain metastases, with a 40% to 55% incidence of CNS failure after a median follow-up of 3 years (4, 5). These and other data suggest that conventional chemotherapeutic agents may not cross the intact blood–brain barrier efficiently, leaving the brain relatively at risk for lung cancer relapse, whereas other systemic sites are effectively treated by chemotherapy (6). As systemic therapies for NSCLC continue to improve, prevention and control of brain metastases is likely to emerge as a more vital therapeutic strategy of overall disease control and improved quality of life.
Gefitinib and erlotinib are orally available, reversible inhibitors of the tyrosine kinase domain of the EGF receptor (EGFR) that have shown efficacy in patients with relapsed NSCLC and as initial therapy for patients with advanced NSCLC and sensitizing EGFR mutations (7, 8). Prospective trials for patients with previously untreated, EGFR-mutant advanced NSCLC have shown response rates of 55% to 75% and progression-free survival of 9 to 13 months for those given gefitinib or erlotinib, approximately 2-fold greater than the results in similar patients treated with chemotherapy (7, 911). These results have led to the approval of gefitinib in Europe for patients with sensitizing mutations of EGFR in all lines of therapy; erlotinib is recommended as initial treatment for patients with sensitizing EGFR mutations in the National Comprehensive Cancer Network guidelines (12, 13).
Evidence from prospective reports has shown that gefitinib and erlotinib can cause regression of established brain metastases from NSCLC, with intracranial response rates reaching 75% in treatment-naive patients with NSCLC with mutated EGFR and synchronous brain metastases (14, 15). These data suggest that in a molecularly selected population with brain metastases, gefitinib and erlotinib can achieve high response rates in metastatic brain tumors that have not traditionally been sensitive to conventional chemotherapeutic agents. However, there is incomplete data about the potential impact of EGFR-TKIs on the prevention and control of CNS metastases caused by NSCLC. A CNS-specific pharmacokinetic resistance as a result of poor CSF penetration of gefitinib and erlotinib in the absence of classical genetic mechanisms of acquired resistance to EGFR-TKIs (e.g. EGFR T790M) has been described; in published reports, the CSF-to-plasma concentration ratio of either gefitinib or erlotinib was less than 0.01 suggesting that the brain may be a susceptible site for progression of NSCLC targeted by EGFR inhibitors (16, 17). However, our group recently reported on 100 patients with advanced NSCLC and somatic EGFR mutations initially treated with gefitinib or erlotinib and found that the risk of developing CNS metastases and/or progression of preexisting brain lesions was approximately 28% after a median potential follow-up of 42 months (18). The 1- and 2-year cumulative risk of CNS progression was 7% and 19%, respectively. These results are substantially less than the published rates of CNS failure in historical series of patients with stage III NSCLC treated with chemotherapy plus chest irradiation and/or surgery as part of a multimodality approach (4, 5). However, the contributing effects of EGFR-targeted therapy and tumor EGFR genotype on the risk of CNS progression remain undefined.
Screening for somatic mutations of EGFR has been conducted for clinically selected NSCLC patients as part of routine care at our institution since 2004 (19). Therefore, we retrieved information on the clinical presentation and course of our patients with advanced NSCLC and sensitizing EGFR mutations, comparing the risk of CNS progression in those initially treated with gefitinib or erlotinib to the risk in similar patients treated with chemotherapy. In particular, we sought to determine whether the apparent decrease in CNS metastases observed in EGFR-mutant NSCLC patients treated with an EGFR-TKI was because treatment with gefitinib or erlotinib delays or effectively treats micrometastatic brain disease and, therefore, delays or prevents the development of CNS metastases.

Go to:
Patients and Methods

Study design and patients

Patients were eligible for this study if they had stage IV NSCLC or stage I–IIIA NSCLC with systemic relapse and sensitizing EGFR mutations and were treated with gefitinib, erlotinib, or chemotherapy as their initial systemic therapy for advanced NSCLC (20). Patients who had previously undergone definitive treatment for stage I–IIIA NSCLC that subsequently relapsed were included if surgery with curative intent had been conducted, with or without pre- or postoperative radiation therapy and/or chemotherapy. Neoadjuvant or adjuvant chemotherapy or chemotherapy plus chest radiation therapy was allowed if completed more than 12 months before the start of systemic treatment for relapsed disease. Patients who were started on treatment for advanced NSCLC from August 1, 2000, to June 1, 2010, were included in this analysis to assure at least 1 year of potential follow-up.
Patients were identified through a query of patient information for subjects prospectively enrolled in the Clinical Research Information System (CRIS) within the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute (Boston, MA). This patient information has been used for previous reports (18, 21, 22). One hundred and forty-two patients with sensitizing EGFR mutations were eligible for inclusion in this study; 73 of these patients have been studied and included in our prior publication on the rates of CNS progression in patients with EGFR-mutant advanced NSCLC initially treated with a tyrosine kinase inhibitor of the EGFR (18). One hundred and thirty-two additional patients who were initially treated with chemotherapy for advanced lung adenocarcinoma and who had not previously undergone EGFR mutation screening were identified. Of the 132 patients, 57 had adequate biopsy specimens available in the Department of Pathology at Brigham and Women’s Hospital (Boston, MA) and were referred for EGFR sequencing to increase the number of EGFR-mutant patients initially treated with chemotherapy. Sensitizing mutations of EGFR were shown in 5 of those 57 patients. Therefore, 147 patients from our institution were included in this analysis. Eight additional EGFR mutation–positive patients who had met all of the above eligibility criteria were reported by investigators from the Beth Israel Deaconess Medical Center (Boston, MA), a member of the Dana-Farber/Harvard Cancer Center. Seven of these 8 patients have been studied and included in prior publications (18, 21, 23). Thus, 155 patients were included in this analysis, which represent 62% of the 252 patients with somatic mutations of EGFR enrolled into both institutions’ databases during the years of the study. Ninety-seven patients with EGFR-mutant NSCLC were excluded from this analysis because of nonsensitizing EGFR mutations (defined later in this section, n = 21); early-stage NSCLC without systemic relapse following definitive therapy (n = 39); stage III NSCLC treated with definitive chemoradiotherapy (n = 13); neoadjuvant or adjuvant chemotherapy completed less than 12 months before the start of systemic therapy for relapsed disease (n = 5); advanced NSCLC not treated with systemic therapy (n = 11); treatment with erlotinib in the adjuvant setting (n = 3); or first-line systemic treatment of advanced NSCLC with chemotherapy plus erlotinib (n = 4), or other investigational EGFR-TKI (n = 1). The patients included in this report provided written informed consent for the collection of baseline clinical information, analysis of their tumor specimens, and collection of clinical outcomes information.

Mutation analysis

Tumor specimens were analyzed for the presence of somatic mutations of EGFR by Sanger dideoxy terminator sequencing of exons 18 to 21 according to previously described methods, with enhanced sensitivity for exon 19 and 21 mutations achieved by the use of specific peptide nucleic acid probes to inhibit amplification of wild-type sequence (24, 25). For those samples (n = 4) that were deemed inadequate for conventional sequencing on the basis of review by a molecular pathologist (Neal I. Lindeman) and/or specimens with a low tumor content, SURVEYOR analysis was used as an alternate method of EGFR mutation detection, using techniques that have been previously reported (26). For the purposes of this study, the following EGFR mutations were considered sensitizing: deletions in exon 19, duplications in exon 19, deletion-insertions of exon 19, L858R point mutation, L861Q point mutation, and G719 missense point mutations (27).

Statistical methods

For all patients, medical records were reviewed to extract data on clinicopathologic characteristics. Tumor histology was classified using the 2004 WHO criteria (28). The distribution of baseline patient characteristics was compared between the treatment groups using Wilcoxon rank-sum test or Fisher exact test.
Data was collected on the prevalence, incidence, and time to development of brain and leptomeningeal metastases from the start of systemic treatment for advanced NSCLC. All patients underwent brain imaging at the time of initial diagnosis of NSCLC and/or at the recognition of advanced disease. Subsequent brain imaging was obtained at the discretion of the treating providers and was generally prompted by symptoms or signs suggestive of CNS involvement. Patients were most frequently evaluated by MRI of the brain, although in some cases, contrast-enhanced computed tomography (CT) was obtained instead of an MRI. CNS metastases included all cases of parenchymal brain metastases and cytologically and/or radiographically diagnosed leptomeningeal disease as previously described (18). Patients classified as having CNS progression included those with newly developed CNS metastases and/or progression of preexisting brain lesions.
Cumulative incidence curves were used to estimate the cumulative risk of CNS progression, and Gray test was used to compare the treatment groups (29). Death without evidence of CNS progression was considered a competing risk in the analysis. If greater than 3 months had elapsed between the date of last clinical follow-up and death without evidence of CNS progression, patients were censored at their time of last clinical follow-up in the analysis of CNS progression. Time to CNS progression and overall survival were estimated using the Kaplan–Meier method, and were calculated from the first day systemic treatment for advanced NSCLC was initiated. The outcome was censored if a patient had not progressed or died at the time of last follow-up. Survival curves were compared by the log-rank test. Competing risks regression based on the proportional subdistribution hazards model was used to estimate the HR for developing CNS progression in the EGFR-TKI versus chemotherapy groups (30). The development of CNS progression was modeled as a time-varying covariate for estimating the associated risk of death by proportional hazards regression. All reported P values are based on 2-sided hypothesis tests. The statistical analysis was computed using SAS 9.2 (SAS Institute Inc.) and the cmprsk package in R version 2.6.2 (R Found Stat Comput).


Go to:
Results

Patient characteristics

Between August 1, 2000, and June 1, 2010, 155 patients with stage IV or relapsed metastatic NSCLC harboring a sensitizing mutation of EGFR were treated with either gefitinib or erlotinib (n = 101) or chemotherapy (n = 54) as their initial systemic therapy for advanced NSCLC. Our center began routine characterization of EGFR in 2004, and has offered protocols of first-line EGFR-TKI therapy for advanced NSCLC since 2002, and for patients with sensitizing EGFR mutations since 2005; thus, few EGFR mutation–positive advanced NSCLC patients were treated with upfront chemotherapy during the years of the study. Table 1 shows the demographic and clinical characteristics of the patients according to the initial treatment group. The median age of the study cohort was 61 years (range, 32–85 years) and did not vary significantly by treatment group. There were 44 men and 111 women, and 73% of patients were never or light smokers. Thirty patients included in the EGFR-TKI group were enrolled in prospective trials of first-line erlotinib that selected patients on the basis of clinical features commonly associated with EGFR mutations (23, 31). As a result, the proportion of women (77% vs. 61%; P = 0.04) and never-smokers (57% vs. 37%; P =0.02) was higher in the EGFR-TKI group compared with the chemotherapy group. Most patients were White, non-Hispanic, although the EGFR-TKI group included a higher percentage of Asian patients (12% vs. 0%; P < 0.01). The majority of patients had stage IV disease at the time of initial diagnosis of NSCLC (84%) and adenocarcinoma histology (90%). Twenty-five patients had previously undergone definitive treatment for stage I–IIIA NSCLC that subsequently relapsed (16 patients with stage I, 4 with stage II, and 5 with stage IIIA) after a median of 41 months (range, 5–82 months). All patients had undergone resection with curative intent, and 7 of the 25 patients had been treated with neoadjuvant or adjuvant chemotherapy (n =5) and/or radiation therapy (n = 6).
Table 1
Baseline patient characteristics


Twenty-four patients (24%) in the EGFR-TKI group and 12 patients (22%) in the chemotherapy group had brain metastases at the time of diagnosis of advanced NSCLC, before the initiation of first-line systemic therapy (P = 1.000). In the EGFR-TKI group, 20 of the 24 patients were treated with whole brain radiation therapy (WBRT) to doses of 3,000 to 4,050 cGy; 2 of the 20 patients were also treated with stereotactic radiosurgery (SRS) following WBRT. One patient with 3 brain metastases was treated with SRS alone. Another patient underwent resection of a single brain metastasis followed by WBRT. In the chemotherapy group, 6 of 12 patients were treated with WBRT. A single brain metastasis was resected in 3 patients, followed by WBRT in 2 patients or SRS to the surgical cavity in one patient. Another patient with multiple brain metastases underwent resection of a symptomatic cerebellar mass followed by WBRT and SRS to residual lesions. The 4 remaining patients (EGFR-TKI: 2; chemotherapy: 2) had asymptomatic brain metastases measuring 6 mm or less and received no localized CNS therapy before their physicians elected to treat them with erlotinib (n = 2) or carboplatin plus paclitaxel (n = 2). Notably, 7 of 12 patients (58%) in the chemotherapy group had a single brain metastasis on contrast-enhanced cranial MRI, compared with 3 of 24 patients (13%) in the EGFR-TKI group, explaining, at least in part, the larger proportion of patients who underwent surgical resection followed by postoperative radiation in the chemotherapy group.
EGFR mutation data were available for all patients included in this analysis (Table 2). EGFR mutation analysis was conducted on a pretreatment tissue specimen in 129 patients, whereas a rebiopsy specimen was tested in 15 patients following treatment with an EGFR-TKI. A specimen date was not available in 11 patients. The proportions of classical mutations (deletions or deletion-insertions of exon 19, L858R point mutation) were similar between the 2 groups. All 8 patients with EGFR T790M had concurrent sensitizing EGFR mutations. Seven of the 8 patients had a clinical response to gefitinib (n =2) or erlotinib (n =5) for a median of 18 months (range, 10–33 months) before showing evidence of progressive disease that harbored both a sensitizing mutation and the resistant T790M mutation on repeat biopsy. Three of the 7 patients had initially been treated with chemotherapy for advanced NSCLC before receiving gefitinib (n = 1) or erlotinib (n = 2). A pretreatment tissue specimen from these 7 patients was either not available or contained insufficient tumor material for EGFR mutation analysis. In these 7 cases, the T790M mutation was presumed secondary and assumed not to be present before an EGFR-TKI was initiated. The remaining patient had de novo EGFR T790M without prior exposure to an EGFR-TKI or systemic chemotherapy.
Table 2
EGFR gene mutations identified



Patterns of disease progression

At the time of this analysis (June 1, 2011), there were 49 patients alive (EGFR-TKI: 36; chemotherapy: 13) with a median follow-up of 30 months (range, 9–97 months). Median follow-up for all eligible patients was 25 months (range, 1–97 months). The follow-up times did not differ significantly between the 2 treatment groups. All but 7 patients had progressive disease or died (EGFR-TKI: 6; chemotherapy: 1). As of the data cutoff point, 18 of the 101 patients in the EGFR-TKI group were continuing to receive their first-line EGFR-TKI (erlotinib in all patients); all patients in the chemotherapy group had discontinued their initial regimen, and 49 of the 54 later received an EGFR-TKI at a median of 6 months (range, 21 days–40 months) from the start of chemotherapy for advanced NSCLC (second-line: 36 patients; third-line: 8 patients; fourth-line: 3 patients; fifth-line: 2 patients). Thirteen of the 36 patients who received second-line treatment with an EGFR-TKI did so before they had radiographic evidence of disease progression, after the identification of a sensitizing mutation of EGFR. Five patients were never treated with an EGFR-TKI. Of those 5 patients, 2 died shortly after the identification of a sensitizing EGFR mutation, before erlotinib could be initiated; another patient encountered delays in obtaining erlotinib because he was unable to secure second party support (insurance) in a timely fashion for purchase of the drug and passed away; and a sensitizing mutation of EGFR was retrospectively identified in 2 patients prompted by this study.
Progression in the CNS occurred in 33 of 101 patients (33%) in the EGFR-TKI group and 26 of 54 patients (48%) in the chemotherapy group. Of the 59 patients who developed CNS progression, 16 had a history of previously treated brain metastases (EGFR-TKI: 9; chemotherapy: 7), whereas 43 did not. Leptomeningeal metastases occurred in 8 patients (8%) in the EGFR-TKI group, and 4 patients (7%) in the chemotherapy group; 8 of these 12 patients had synchronous brain metastases at the time of diagnosis of leptomeningeal involvement. The CNS was the initial site of progression on gefitinib or erlotinib in 8 patients, and the sole site of initial failure in 2 of these 8 patients. The respective numbers for the chemotherapy group were 8 patients as the initial site of progression and 2 as the only site of failure.
The cumulative incidence curves of CNS progression for each group are shown in Fig. 1. The cumulative risk of CNS progression at 6, 12, and 24 months was 1%, 6%, and 21%, respectively, in the EGFR-TKI group, and 7%, 19%, and 32% in the chemotherapy group (P = 0.026, Fig. 1A). When the analysis was narrowed to only those 119 patients without preexisting brain metastases, the 6-, 12- and 24-month cumulative rates of CNS progression were 1%, 3%, and 15% in the EGFR-TKI group, compared with corresponding rates of 7%, 17%, and 30% in the chemotherapy group (P = 0.032, Fig. 1B). The time to the occurrence of CNS progression from the start of systemic treatment for advanced NSCLC was significantly longer in the EGFR-TKI group than in the chemotherapy group, with a median of 56.0 months versus 31.6 months (P = 0.010). The HR of CNS progression for upfront EGFR-TKI versus chemotherapy was 0.56 [95% confidence interval (CI), 0.34–0.94], suggesting a risk reduction of 40%. Because the cohort of patients initially treated with an EGFR-TKI was enriched for women and never-smokers compared with patients treated with upfront chemotherapy, we confirmed that the effect of upfront EGFR-TKI versus chemotherapy retained significance in a multivariate model that adjusted simultaneously for the impacts of gender, smoking history, and prior CNS involvement (adjusted HR, 0.52; 95% CI, 0.32–0.87).
Figure 1
Cumulative incidence of CNS progression in (A) all eligible patients, (B) patients without prior CNS involvement, and (C) patients with prior CNS involvement.


The overall survival did not differ significantly between the 2 treatment groups. The median survival times were 31.0 months for the EGFR-TKI group and 29.8 months for the chemotherapy group (P = 0.131; Fig. 2). The development of CNS progression was associated with a 4- to 5-fold increase in the risk of death in both treatment groups (P < 0.001). The median survival after the diagnosis of CNS progression was 5.9 and 10.3 months in the EGFR-TKI and chemotherapy groups, respectively (P = 0.608).
Figure 2
Overall survival in all eligible patients. OS, overall survival.




Go to:
Discussion

We retrospectively analyzed the impact of initial gefitinib or erlotinib therapy versus chemotherapy on the risk of CNS progression in patients with advanced NSCLC with mutated EGFR, and found a significantly lower cumulative risk of CNS progression in patients initially treated with a tyrosine kinase inhibitor of the EGFR compared with chemotherapy. The 6-, 12-, and 24-month cumulative risk of CNS progression was 1%, 6%, and 21% for the EGFR-TKI group compared with 7%, 19%, and 32% for the chemotherapy group (P = 0.026), and the cause specific HR for EGFR-TKI versus chemotherapy was 0.56 (95% CI, 0.34–0.94), suggesting a risk reduction of 40%. To our knowledge, this is the first retrospective study examining the impact of upfront EGFR-targeted therapy versus conventional chemotherapy on the risk of CNS progression in patients with sensitizing EGFR mutations, and it offers important insights into the management of this, and potentially other, molecularly defined subset(s) of patients with NSCLC.
The introduction of agents directed against the EGFR has notably expanded the available therapeutic options for patients with advanced NSCLC. In the present study, we extend the data from our prior publication suggesting lower rates of CNS progression (compared with historical estimates) in EGFR-mutant advanced NSCLC patients initially treated with gefitinib or erlotinib, and find that the observed lower frequency of CNS metastases seems to be due, at least in part, to the effect of the EGFR-TKI (18). Notably, the lower cumulative rates of CNS progression in the EGFR-TKI group were largely related to a lower risk of CNS metastases in patients without prior CNS involvement (P =0.032) and persisted despite high crossover (91%) to EGFR-targeted therapy in patients initially treated with chemotherapy. The time to the occurrence of CNS progression was also significantly prolonged in the EGFR-TKI group (56.0 vs. 31.6 months, P =0.010), hinting at the potential of gefitinib and erlotinib at slowing the rate of development of CNS metastases from NSCLC. Whether gefitinib and erlotinib can penetrate into the CNS sufficiently to treat micrometastatic CNS disease from NSCLC and thereby prevent the outgrowth of CNS metastases, however, remains uncertain. Previous studies have shown that CNS penetration of erlotinib and gefitinib at standard daily dosing is limited, and authors have suggested that incomplete drug penetration into the CNS may ultimately permit CNS failure in patients with NSCLC treated with gefitinib or erlotinib (17, 32). Investigating the patterns of failure in patients with resected NSCLC and EGFR mutations undergoing adjuvant chemotherapy with or without an EGFR-TKI may help elucidate this issue. This approach would allow an evaluation of the limitations of primary therapy, and may help define subgroups of patients who perhaps should be treated differently because of a different natural history. Our observations also highlight the importance of elucidating the potential CNS efficacy of novel therapeutic agents. This may be of relevance for designing phase I trials of targeted therapy because the paradigm has been shifting from establishing the maximum tolerated dose to establishing the optimal biologic dose, which may not achieve adequate CNS concentrations (33). The dosing schedule may also be pertinent, for example pulsatile versus continuous (16).
The significance of EGFR mutations as a risk factor for CNS progression in NSCLC has not yet been clearly defined. In our study, the risk of CNS progression was not independently examined in a NSCLC cohort without EGFR mutations, thereby limiting our ability to evaluate a possible altered biologic predisposition of EGFR mutated lung cancer for CNS sites. The significance of EGFR mutations on the outcome of CNS progression might be best evaluated in a study with an untreated control arm to distinguish therapeutic effect from underlying tumor biology. One such retrospective surgical series of 117 patients suggested that isolated recurrence in the brain following complete resection of the primary NSCLC was more frequent in patients with tumors bearing an EGFR mutation (mutated vs. wild-type EGFR, 24% vs. 9%; P = 0.15) after a median follow-up of 40 months (34). Given the modest numbers, this did not reach statistical significance. Nonetheless, these data suggest that the lower rates of CNS progression in patients initially treated with an EGFR-TKI in our study might reflect an even more significant alteration in the potential course of disease for patients with EGFR mutations.
Our findings are limited to those of any retrospective analysis. First, the observed frequency and patterns of CNS progression were subject to the frequency and thoroughness of clinical and radiographic evaluation. For example, asymptomatic CNS lesions were not specifically sought after, and radiologic confirmation of clinical suspicion was necessary for the identification of CNS progression. However, in the absence of a systematic bias between the 2 treatment groups, our observations should be valid. Similarly, we could not evaluate an interaction between performance status and CNS progression due to the small number of patients with a performance status of 2 or more in both treatment groups (12 of 155, or 8%). Certainly, more prospective study of the topic of CNS progression with scheduled CNS imaging is warranted. Such study could also help define whether surveillance of the brain for early detection of CNS metastases could be useful in patients with EGFR-mutant NSCLC.
Our findings also have potentially broader implications, as the armamentarium for personalized therapies expands in lung cancer and other solid malignancies. Anaplastic lymphoma kinase (ALK) is one of the newest molecular targets in NSCLC, and rearrangement of the ALK gene defines a subset of NSCLC sensitive to therapeutic ALK inhibition, resulting in significantly improved outcomes for these patients, analogous to those observed for NSCLC patients with EGFR mutations treated with an EGFR-TKI (35). Data from an expansion cohort of a phase I trial of the ALK tyrosine kinase inhibitor crizotinib showed 1- and 2-year overall survival rates of 74% and 54%, respectively, in 82 ALK-positive advanced NSCLC patients treated with crizotinib (36). However, a recent case report suggested limited CSF penetration of crizotinib at standard twice daily dosing, with a CSF-to-plasma concentration ratio less than 0.5% and a crizotinib CSF concentration below the concentration required to inhibit growth of cell lines harboring an EML4-ALK translocation by 50% (37). Thus, information will be needed to assess whether the prolonged survival observed in NSCLC patients with ALK translocations treated with crizotinib translates into an increased cumulative risk of CNS progression.
In summary, our results suggest lower rates of CNS progression in EGFR-mutant advanced NSCLC patients initially treated with gefitinib or erlotinib compared with upfront chemotherapy. If validated, our findings suggest that gefitinib and erlotinib may be effective at delaying and/or preventing CNS metastases from NSCLC in patients with sensitizing EGFR mutations. As new genomically defined subsets of NSCLC are identified that can be targeted with small-molecule inhibitors, such as ALK-rearranged lung cancers responsive to crizotinib, there is a need to conduct carefully designed trials with specific CNS endpoints to evaluate candidates for targeted therapy in terms of CNS penetration, and whether they can treat established CNS metastases and/or prevent them for occurring or recurring.

Go to:
Translational Relevance


Central nervous system (CNS) metastases caused by non–small cell lung cancer (NSCLC) remain a frequent complication, and their occurrence has been altered little by cytotoxic chemotherapy. The EGF receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib, can penetrate into the CNS and elicit intracranial responses in patients with CNS metastases from NSCLC, but their impact on the outcome of CNS progression remains an area of investigation. Our data suggest that initial treatment of EGFR-mutant advanced NSCLC patients with gefitinib or erlotinib significantly lowers the risk of CNS progression during the disease course compared with chemotherapy and hint at the potential of these agents at delaying and/or preventing CNS metastases from NSCLC. As advances in systemic therapy are being made in other genetic subpopulations of NSCLC and other primary tumor types, our observations highlight the importance of studying novel agents in terms of penetration into the CNS.



Go to:
Acknowledgments

Grant Support
This work was funded in part by the American Society of Clinical Oncology (ASCO) Cancer Foundation Translational Research Professorship (to B.E. Johnson), NIH grant 5R01-CA114465 (to B.E. Johnson and B.Y. Yeap), ASCO Conquer Cancer Foundation Career Development Award (to D.B. Costa), the Alice and Stephen D. Cutler Investigator Fund in Thoracic Oncology at Dana-Farber Cancer Institute (to D.M. Jackman and S. Heon), and the Elaine Promisel Siegel Fund in Thoracic Oncology at Dana-Farber Cancer Institute (to S. Heon).


Go to:
Footnotes


Disclosure of Potential Conflicts of Interest
V.A. Joshi: employment (KEW Group); ownership interest (KEW Group). D.B. Costa: consultant/advisory board (Pfizer; AstraZeneca; Roche). M.S. Rabin: consultant/advisory board (Genentech). D.M. Jackman: consultant/advisory board (Foundation Medicine; Genentech). B.E. Johnson: ownership interest (KEW Group); consultant/advisory board (Genentech; Pfizer; Chugai; AstraZeneca); post marketing royalties for EGFR mutation testing. No potential conflicts of interest were disclosed by the other authors.
Authors’ Contributions
Conception and design: S. Heon, B.Y. Yeap, N. Lindeman, D.M. Jackman, B.E. JohnsonDevelopment of methodology: S. Heon, V.A. Joshi, B.E. Johnson
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): S. Heon, N. Lindeman, V.A. Joshi, M. Butaney, D. B. Costa, M.S. Rabin, D.M. Jackman
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): S. Heon, B.Y. Yeap, N. Lindeman, D.B. Costa, B.E. Johnson
Writing, review, and/or revision of the manuscript: S. Heon, B.Y. Yeap, N. Lindeman, V.A. Joshi, D.B. Costa, M.S. Rabin, D.M. Jackman, B.E. Johnson
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): S. Heon, M. Butaney, G.J. Britt, M.S. Rabin, B.E. Johnson
Study supervision: S. Heon, B.E. Johnson



Go to:
References

1. Langer CJ, Mehta MP. Current management of brain metastases, with a focus on systemic options. J Clin Oncol. 2005;23:6207–19. [PubMed]
2. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92–8. [PubMed]
3. Scagliotti GV, De Marinis F, Rinaldi M, Crino L, Gridelli C, Ricci S, et al. Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol. 2002;20:4285–91. [PubMed]
4. Chen AM, Jahan TM, Jablons DM, Garcia J, Larson DA. Risk of cerebral metastases and neurological death after pathological complete response to neoadjuvant therapy for locally advanced nonsmall-cell lung cancer: clinical implications for the subsequent management of the brain. Cancer. 2007;109:1668–75. [PubMed]
5. Mamon HJ, Yeap BY, Janne PA, Reblando J, Shrager S, Jaklitsch MT, et al. High risk of brain metastases in surgically staged IIIA non-small-cell lung cancer patients treated with surgery, chemotherapy, and radiation. J Clin Oncol. 2005;23:1530–7. [PubMed]
6. Pitz MW, Desai A, Grossman SA, Blakeley JO. Tissue concentration of systemically administered antineoplastic agents in human brain tumors. J Neuro Oncol. 2011;104:629–38. [PubMed]
7. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–8. [PubMed]
8. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123–32. [PubMed]
9. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121–8. [PubMed]
10. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–57. [PubMed]
11. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735–42. [PubMed]
12. European Medicines Agency. Iressa: Gefitinib - EPAR summary for the public. [cited September 5, 2011]. Available from: http://www.ema.europa.eu/docs/en_GB/...C500036359.pdf.
13. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Non-small cell lung cancer. [cited January 31, 2012]. http://www.nccn.org/professionals/ph...s/pdf/nscl.pdf.
14. Ceresoli GL, Cappuzzo F, Gregorc V, Bartolini S, Crino L, Villa E. Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol. 2004;15:1042–7. [PubMed]
15. Porta R, Sanchez-Torres JM, Paz-Ares L, Massuti B, Reguart N, Mayo C, et al. Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J. 2011;37:624–31. [PubMed]
16. Grommes C, Oxnard GR, Kris MG, Miller VA, Pao W, Holodny AI, et al. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol. 2011;13:1364–9. [PMC free article] [PubMed]
17. Jackman DM, Holmes AJ, Lindeman N, Wen PY, Kesari S, Borras AM, et al. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J Clin Oncol. 2006;24:4517–20. [PubMed]
18. Heon S, Yeap BY, Britt GJ, Costa DB, Rabin MS, Jackman DM, et al. Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clin Cancer Res. 2010;16:5873–82. [PMC free article] [PubMed]
19. Sequist LV, Martins RG, Spigel D, Grunberg SM, Spira A, Janne PA, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol. 2008;26:2442–9. [PubMed]
20. Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol. 2007;2:706–14. [PubMed]
21. Costa DB, Nguyen KS, Cho BC, Sequist LV, Jackman DM, Riely GJ, et al. Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib. Clin Cancer Res. 2008;14:7060–7. [PMC free article] [PubMed]
22. Jackman DM, Yeap BY, Sequist LV, Lindeman N, Holmes AJ, Joshi VA, et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolongedsurvival innon-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res. 2006;12:3908–14. [PubMed]
23. Jackman DM, Cioffredi LA, Lindeman N, Morse LK, Lucca J, Weckstein D, et al. Phase II trial of erlotinib in chemotherapy-naive women with advanced pulmonary adenocarcinoma. J Clin Oncol. 2009;27:15s. (suppl; abstr 8065)
24. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39. [PubMed]
25. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500. [PubMed]
26. Janne PA, Borras AM, Kuang Y, Rogers AM, Joshi VA, Liyanage H, et al. A rapid and sensitive enzymatic method for epidermal growth factor receptor mutation screening. Clin Cancer Res. 2006;12:751–8. [PubMed]
27. Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Janne PA, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol. 2010;28:357–60. [PubMed]
28. Beasley MB, Brambilla E, Travis WD. The 2004 World Health Organization classification of lung tumors. Semin Roentgenol. 2005;40:90–7. [PubMed]
29. Gray RJ. A class of K-Sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141–54.
30. Jason PF, Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing Risk. J Am Stat Assoc. 1999;94:496–509.
31. Janne PA, Wang X, Socinski MA, Crawford J, Stinchcombe TE, Gu L, et al. Randomized Phase II Trial of Erlotinib Alone or With Carboplatin and Paclitaxel in Patients Who Were Never or Light Former Smokers With Advanced Lung Adenocarcinoma: CALGB 30406 Trial. J Clin Oncol. 2012;30:2063–9. [PMC free article] [PubMed]
32. Togashi Y, Masago K, Fukudo M, Terada T, Fujita S, Irisa K, et al. Cerebrospinal fluid concentration of erlotinib and its active metabolite OSI-420 in patients with central nervous system metastases of non-small cell lung cancer. J Thorac Oncol. 2010;5:950–5. [PubMed]
33. Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst. 2009;101:708–20. [PMC free article] [PubMed]
34. Lee YJ, Park IK, Park MS, Choi HJ, Cho BC, Chung KY, et al. Activating mutations within the EGFR kinase domain: a molecular predictor of disease-free survival in resected pulmonary adenocarcinoma. J Cancer Res Clin Oncol. 2009;135:1647–54. [PubMed]
35. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693–703. [PMC free article] [PubMed]
36. Shaw AT, Yeap BY, Solomon BJ, Riely GJ, Gainor J, Engelman JA, et al. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol. 2011;12:1004–12. [PMC free article] [PubMed]
37. Costa DB, Kobayashi S, Pandya SS, Yeo WL, Shen Z, Tan W, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011;29:e443–5. [PubMed]
'lizbeth is offline   Reply With Quote
Old 10-08-2013, 11:50 PM   #2
gdpawel
Senior Member
 
gdpawel's Avatar
 
Join Date: Aug 2006
Location: Pennsylvania
Posts: 1,080
New Targets in Breast Cancer Therapy

Dr. Robert Nagourney
Medical and Laboratory Director
Rational Therapeutics, Inc.
Long Beach, California

In many ways the era of targeted therapy began with the recognition that breast cancers expressed estrogen receptors, the original work identified the presence of estrogen receptors by radioimmunoassay. Tumors positive for ER tended to be less aggressive and appear to favor bone sites when they metastasized. Subsequently, drugs capable of blocking the effects of estrogen at the estrogen receptor were developed. Tamoxifen competes with estrogen at the level of the receptor. This drug became a mainstay with ER positive tumors and continues to be used today, decades after it was first synthesized.

Recognizing that some patients develop resistance to Tamoxifen, additional classes of drugs were developed that reduced the circulating levels of estrogen by inhibiting the enzyme aromatase, this enzyme found in adipose tissue, converts steroid precursors to estrogen. Despite the benefits of these classes of drugs known as SERMS (selective receptor modulators), many patients break through hormonal therapies and require cytotoxic chemotherapy.

With the identification of HER-2 amplification, a new subclass of breast cancers driven by a mutation in the growth factor family provided yet a new avenue of therapy – trastuzumab (Herceptin). For HER-2 positive breast cancers Herceptin has dramatically changed the landscape. Providing synergy with chemotherapy this monoclonal antibody has also been applied in the adjuvant setting offering survival advantage in those patients with the targeted mutation.

Reports from the San Antonio breast symposium held in Texas last December, provide two new findings.

The first is a clinical trial testing the efficacy of Perjeta (pertuzumab). This novel monoclonal antibody functions by preventing dimerization of HER-2 (The target of Herceptin) with the other members of the human epidermal growth factor family HER-1, HER-3 and HER-4. In so doing, the cross talk between receptors is abrogated and downstream signaling in squelched.

The second important finding regards the use of everolimus. This small molecule derivative of rapamycin blocks cellular signaling through the mTOR pathway. Combining everolimus with the aromatase inhibitor exemestane, improved time to progression.

While these two classes of drugs are different, the most interesting aspect of both reports reflects the downstream pathways that they target. Perjeta (pertuzumab) inhibits signaling at the PI3K pathway, upstream from mTOR. Everolimus blocks mTOR itself, thus both drugs are influencing cell signaling that channel through metabolic pathways PI3K is the membrane signal from insulin, while mTOR is an intermediate in the same pathway.

Thus, these are in truest sense of the word, breakthroughs in metabolomics.

Much like genomics aims to unravel the structure of the genome, metabolomics focuses on understanding the many small molecule metabolites that result from a cell’s metabolic processes.

There are an estimated 5,000 - 20,000 endogenous human metabolites, and analysing their production gives an accurate picture of the physiology of a cell at a given moment in time. Whereas the cell’s genotype can predict its physiology to a limited extent, metabolomics also takes phenotype – and therefore environmental conditions – into account, allowing a more precise measure of actual cell physiology.

For research, the study of metabolomics provides the means to measure the effects of a variety of stimuli on individual cells, tissues, and bodily fluids.

By studying how their metabolic profiles change with the introduction of chemicals or the expression of known genes, for example, researchers can more effectively study the immediate impact of disease, nutrition, pharmaceutical treatment, and genetic modifications while using a systems biology approach.
gdpawel is offline   Reply With Quote
Old 10-08-2013, 11:53 PM   #3
gdpawel
Senior Member
 
gdpawel's Avatar
 
Join Date: Aug 2006
Location: Pennsylvania
Posts: 1,080
Why Do Some Breast Cancers Stop Responding to Targeted Therapy?

Targeted therapy halts the growth of certain cancers by zeroing in on a signaling molecule critical to the survival of those cancer cells. The drugs are effective in about 10-15% of patients. The drugs work specifically in patients whose cancers contain mutations in a gene that encodes the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) or some other pathway.

The EGFR stands at the origin of a major signaling pathway involved in the growth of breast cancer. Two of the four receptors in this pathway, epidermal growth factor receptor type 1 (HER1) and epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu or ErbB2), are promising targets for new treatments.

In about 20% of patients with breast cancer, the tumor overexpresses HER2. Herceptin, a humanized monoclonal antibody that targets the extracellular domain of HER2, is effective as adjuvant therapy and as treatment for metastatic disease in patients with HER2-positive breast cancer.

Tykerb, an orally administered small-molecule inhibitor of the tyrosine kinase domains of HER1 and HER2, has antitumor activity when used as a single agent in patients with HER2-positive inflammatory breast cancer or HER2-positive breast cancer with central nervous system (CNS) metastases that are refractory to Herceptin. This finding is important because HER2-positive tumors frequently spread to the CNS, where the tumor is sheltered from Herceptin and most chemotherapeutic agents.

Other targeted therapies also show great promise in the treatment of breast cancer. Avastin is a monoclonal antibody against the vascular endothelial growth factor (VEGF). Tumors can be effectively controlled by targeting the network of blood vessels that feed them. Tumor growth is dependent on angiogenesis. Angiogenesis is dependent on VEGF. Avastin directly binds to VEGF to directly inhibit angiogenesis. Within 24 hours of VEGF inhibition, endothelial cells have been shown to shrivel, retract, fragment and die by apoptosis. In addition to VEGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to VEGF.

Although these targeted therapies are initially effective in certain subsets of patients, the drugs eventually stop working, and the tumors begin to grow again. This is called acquired or secondary resistance. This is different from primary resistance, which means that the drugs never work at all. The change of a single base in DNA that encodes the mutant protein has been shown to cause drug resistance.

Initially, tumors have the kinds of mutations in the EGFR or VEGF gene that were previously associated with responsiveness to these drugs. But, sometime tumors grow despite continued therapy because an additional mutation in the gene, strongly implies that the second mutation was the cause of drug resistance. Biochemical studies have shown that this second mutation, which was the same as before, could confer resistance to the EGFR or VEGF mutants normally sensitive to these drugs.

It is especially interesting to note that the mutation is strictly analogous to a mutation that can make it tumor resistant. For example, mutations in a gene called KRAS, which encodes a signaling protein activated by EGFR, are found in 15 to 30 percent of certain cancers. The presence of a mutated KRAS gene in a biopsy sample is associated with primary resistance to drugs. Tumor cells from patients who develop secondary resistance to a drug like Tarceva after an initial response on therapy did not have mutations in KRAS. Rather, these tumor cells had new mutations in EGFR. This further indicates that secondary resistance is very different from primary resistance.

All the EGFR/VEGF mutation or amplification studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if one drug is better or worse than some other drug which may target this. There are differences. The drug has to get inside the cells in order to target anything.

EGFR/VEGF-targeted drugs are poorly-predicted by measuring the ostansible targets, but can be well-predicted by measuring the effect of the drug on the "function" of live cells.

Literature Citation:
PLoS Medicine, February 22, 2005
Eur J Clin Invest 37 (suppl. 1):60, 2007
gdpawel is offline   Reply With Quote
Old 10-08-2013, 11:55 PM   #4
gdpawel
Senior Member
 
gdpawel's Avatar
 
Join Date: Aug 2006
Location: Pennsylvania
Posts: 1,080
Personalized Targeted therapy is still trial-and-error treatment

Although the theory behind targeted therapy is appealing, the reality is more complex. For example, cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes.

In other words, cancer cells have 'backup systems' that allow them to survive. The result is that the drug does not shrink the tumor as expected. One approach to this problem is to functionally target multiple pathways in a cancer cell.

Another challenge is to identify which of the targeted treatments will be effective (enzyme inhibitors, proteasome inhibitors, angiogenesis inhibitors, and monoclonal antibodies).

Targeted therapy is still trial-and-error treatment.

The functional profiling platform can explore multiple signaling pathways from the same test. It doesn't have to test for each and every signaling pathways there are.

There are many pathways to altered cellular function. Testing for these pathways, those which identify DNA, or RNA sequences or expression of individual genes or proteins often examine only one component of a much larger, interactive process. In testing for all "known" mutations, if you miss just one, it may be the one that gets through.

And it's not just only targeted drugs that may be effective as first-line treatment on your individual cancer cells. Cancers share pathways across tumor types. There really is no lung cancer chemos, or breast cancer chemos, or ovarian cancer chemos.

There are chemos that are sensitive (effective) or there are chemos that are resistant (ineffective) to each and every "individual" cancer patient, not populations. There are chemos that share across tumor types.

The functional profiling platform has the unique capacity to identify all of the operative mechanisms of response and resistance by gauging the result of drug exposure at its most important level: cell death.

Finding what targeted therapies would work for what cancers is very difficult. A lot of trial-and-error goes along trying to find out. However, finding the right targeted therapies for the right "individual" cancer cells can be improved by cell-based assays, using functional profiling.

Identifying DNA expression of individual proteins (that measure of RNA content, like Her2, EGFR, KRAS or ALK) often examine only one component of a much larger, interactive process. Gene (molecular) profiling measures the expression only in the "resting" state, prior to drug exposure. There is no single gene whose expression accurately predicts clinical outcome. Efforts to administer targeted therapies in randomly selected patients often will result in low response rates at significant toxicity and cost.

All DNA or RNA-type tests are based on "population" research (not individuals). They base their predictions on the fact that a higher percentage of people with similar genetic profiles or specific mutations may tend to respond better to certain drugs. This is not really "personalized" medicine, but a refinement of statistical data.

Functional profiling measures proteins before and after drug exposure. It measures what happens at the end (the effects on the forest), rather than the status of the individual trees. Molecular profiling is far too limited in scope to encompass the vagaries and complexities of human cancer biology when it comes to drug selection. The endpoints of molecular profiling are gene expression. The endpoints of functional profiling are expression of cell death (both tumor cell death and tumor associated endothelial [capillary] cell death).

In testing for all "known" mutations, if you miss just one, it may be the one that gets through. And it's not just only targeted drugs that may be effective as first-line treatment on your "individual" cancer cells. Cancers share pathways across tumor types.

Targeted treatments take advantage of the biologic differences between cancer cells and healthy cells by "targeting" faulty genes or proteins that contribute to the growth and development of cancer. Many times these drugs are combined with chemotherapy, biologic therapy (immunotherapy), or other targeted treatments.

Clinicians have learned that the same enzymes and pathways are involved in many types of cancer. However, understanding targeted treatments begins with understanding the cancer "cell." In order for cells to grow, divide, or die, they send and receive chemical messages. These messages are transmitted along specific pathways that involve various genes and proteins in the cell.

Cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes.

Targeted therapies are typically not very effective when used singularly or even in combination with conventional chemotherapies. The targets of many of these drugs are so narrow that cancer cells are likely to eventually find ways to bypass them.

Physicians may have to combine several targeted treatments to try an achieve cures or durable responses for more complicated tumors like those that occur in the breast, colon and lung.

These targeted therapies produce limited results because they can help a relatively small subgroup of cancer patients. But when they work, they produce very good responses. With targeted therapy, the trick is figuring out which patients will respond. Tests to pinpoint those patients cannot be accomplished with genetic testing.

All the gene amplification studies, via genetic testing, tell us is whether or not the cancer cells are potentially susceptible to a mechanism/pathway of attack. They don't tell you if one drug is better or worse than another drug which may target a certain mechanism/pathway. Cell-based functional analysis can accomplish this.

The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not just one target or pathway, or even a few targets/pathways.

Literature Citation:

Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007
Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)
gdpawel is offline   Reply With Quote
Old 10-09-2013, 12:34 PM   #5
gdpawel
Senior Member
 
gdpawel's Avatar
 
Join Date: Aug 2006
Location: Pennsylvania
Posts: 1,080
Re: Targeted Vs Chemo - and targeted wins!

Just complementing/supplementing your posts 'lizbeth.
gdpawel is offline   Reply With Quote
Old 10-09-2013, 04:29 PM   #6
'lizbeth
Senior Member
 
'lizbeth's Avatar
 
Join Date: Apr 2008
Location: Sunny San Diego
Posts: 2,214
Re: Targeted Vs Chemo - and targeted wins!

I think I shared a bit too much of my sarcasm . . . yes, very good information, thanks gdp.
'lizbeth is offline   Reply With Quote
Old 10-09-2013, 05:04 PM   #7
gdpawel
Senior Member
 
gdpawel's Avatar
 
Join Date: Aug 2006
Location: Pennsylvania
Posts: 1,080
Re: Targeted Vs Chemo - and targeted wins!

I don't think I can do on here like you can do on FB. So I'll just Ping! LOL!
gdpawel is offline   Reply With Quote
Old 10-09-2013, 06:55 PM   #8
'lizbeth
Senior Member
 
'lizbeth's Avatar
 
Join Date: Apr 2008
Location: Sunny San Diego
Posts: 2,214
Re: Targeted Vs Chemo - and targeted wins!

GDP, let's talk tyrosine kinase inhibitors. What affect would these have on the neurotransmitter dopamine? How does L-tyrosine affect the tyrosine kinase process?

Can you help me find information on this?
'lizbeth is offline   Reply With Quote
Old 10-09-2013, 07:41 PM   #9
'lizbeth
Senior Member
 
'lizbeth's Avatar
 
Join Date: Apr 2008
Location: Sunny San Diego
Posts: 2,214
Re: Targeted Vs Chemo - and targeted wins!

Well . . . I had typed up a long response and the system logged me out - as usual.

I don't quite agree with this:
Quote:
Targeted therapies are typically not very effective when used singularly or even in combination with conventional chemotherapies. The targets of many of these drugs are so narrow that cancer cells are likely to eventually find ways to bypass them.

Physicians may have to combine several targeted treatments to try an achieve cures or durable responses for more complicated tumors like those that occur in the breast, colon and lung.

These targeted therapies produce limited results because they can help a relatively small subgroup of cancer patients. But when they work, they produce very good responses. With targeted therapy, the trick is figuring out which patients will respond. Tests to pinpoint those patients cannot be accomplished with genetic testing.
I feel comparatively to the success of chemotherapy, targeted treatments have significantly changed the treatments, disease free progression and overall survival for many cancer patient subgroups.

I understand about single use therapies. My good friend failed miserably on a PARP inhibitor. But she had gone through numerous treatments, alternatives. In fact, she is one of the only patients I know that was tested at Rational Therapeutics.

Part of the issue that might come up from functional profiling is to have the physician and patient on board to follow the best recommendation.

When the patient has to switch medical teams frequently to try and get the needed treatments to stay ahead of cancer and they are stage IV, stressed and ill, important decision making information seems to get lost or forgotten. Not everyone has an advocate, or a medical team that is vested in them beating cancer.
'lizbeth is offline   Reply With Quote
Old 10-09-2013, 08:26 PM   #10
gdpawel
Senior Member
 
gdpawel's Avatar
 
Join Date: Aug 2006
Location: Pennsylvania
Posts: 1,080
Re: The tyrosine kinase process

From what I remember, dopamine receptor antagonists inhibit the class of receptors that binds dopamine, a hormone and neurotransmitter. Dopamine is an emetic and can induce nausea, hence blocking dopamine receptors is another treatment of controlling chemotherapy-induced nausea and vomiting. Domperidone (commercially called Motilium) and metoclopramide (Reglan) are the two main dopamine receptor antagonists used for antiemetic treatment. Here is an excellent review on the pharmacokenetics of dopamine receptor antagonists.

http://www.pharmacorama.com/en/Secti...amines_7_4.php

I know there has been some concern about the potential for significant cardiovascular effects of the newer biologic therapies like the tyrosine kinase inhibitor sunitinib (Sutent). Patients and doctors need to get more information and they need to know the potential side effects down the road (a.k.a. tighter monitoring).

In regards to tyrosine kinase, these are very specific enzymes and therefore specific enzyme inhibitors. Most proteins in the body contain tyrosine. But tyrosine is only phosphorylated by a specific tyrosine kinase. Tyrosine is a very general amino acid. It is present everywhere. There are many, many, many tyrosine kinase inhibitors. The effects of these inhibitors is very specific. Therefore, I would not expect that most of the pharmaceutical tyrosine kinase inhibitors would have any effects at all on the neurotransmitter dopamine.
gdpawel is offline   Reply With Quote
Old 10-09-2013, 10:04 PM   #11
gdpawel
Senior Member
 
gdpawel's Avatar
 
Join Date: Aug 2006
Location: Pennsylvania
Posts: 1,080
Re: Targeted Vs Chemo - and targeted wins!

In regards to diagnostics in cancer treatment, some phenotype profiling labs, in addition to testing your tumor against a number of chemotherapeutics, can also test the effectiveness of molecularly targeted agents in treating cancer.

Scientists have come to realize that cancer biology is driven by signaling pathways. Cells speak to each other and the messages they send are interpreted via intracellular pathways known as signal transduction. Picture these pathways as if they were phone lines, linking one cell to another.

Many of these pathways are activated or deactivated by chemical reactions. In some cases, programmed cell death is inhibited when these pathways are disrupted. When the cell does not die, as it should normally, cancer forms.

In recent years, research has lead to the creation of “small molecules” to regulate these chemical reactions. Hundreds of these “targeted" agents are currently in development for cancer treatment.

While some physicians are using genomic or proteomic testing to detect mutations in these pathways, phenotype analysis labs have taken a different approach. Using functional profiling, they measure the end result of pathway activation or deactivation in the individual. They can then predict whether the "individual" cancer patient will "actually" respond to a targeted agent.

To date, their results have exceeded the reported results of those who have based treatment regimens on DNA profiles (Arienti et al. Journal of Translational Medicine 2011, 9:94).
gdpawel is offline   Reply With Quote
Old 10-10-2013, 10:03 AM   #12
'lizbeth
Senior Member
 
'lizbeth's Avatar
 
Join Date: Apr 2008
Location: Sunny San Diego
Posts: 2,214
Re: Targeted Vs Chemo - and targeted wins!

GDP,

I'm totally on board with using functional profiling for the initial selection of treatment.

What confuses me is if a secondary or another primary resistance develops. How is the decision made on what treatment to try next?

Thanks for the information on dopamine and l-tyrosine. I did not realize that (Reglan) was a main dopamine receptor antagonist. It certainly is helpful for a severe case of hiccups too.
'lizbeth is offline   Reply With Quote
Old 10-10-2013, 12:49 PM   #13
gdpawel
Senior Member
 
gdpawel's Avatar
 
Join Date: Aug 2006
Location: Pennsylvania
Posts: 1,080
Drug Resistance

Drug resistance is a major problem with conventional cytotoxic chemotherapy agents. This is because most cancer cells are genetically unstable, are more prone to mutations and are therefore likely to produce drug resistant cells. However, since angiogenic drugs target normal endothelial cells which are not genetically unstable, drug resistance may not develop. So far, resistance has not been a major problem in long-term animal studies or in clinical trials, and neither has it with assay-directed therapy.

Even in previously failed therapies, results from phenotype analysis have seen numerous occasions in which a drug used years earlier becomes effective again, once the tumor has been removed from the selective pressure of drug exposure. The tumor loses the capacity to resist. One can test almost any drug in the laboratory, providing the whole "live" tumor is available. Changes induced by subsequent treatment may bring the tumor back to a point where failed drugs are viable again. A number of these laboratories have tested many small molecules and in the past studied the P-glycoprotein and GST inhibitors to reverse drug resistance.
gdpawel is offline   Reply With Quote
Reply

Thread Tools
Display Modes

Posting Rules
You may not post new threads
You may not post replies
You may not post attachments
You may not edit your posts

BB code is On
Smilies are On
[IMG] code is On
HTML code is On

Forum Jump


All times are GMT -7. The time now is 02:53 PM.


Powered by vBulletin® Version 3.8.7
Copyright ©2000 - 2024, vBulletin Solutions, Inc.
Copyright HER2 Support Group 2007 - 2021
free webpage hit counter