A prospective pharmacogenomic (PG), pharmacodynamic (PD), and pharmacokinetic (PK) study of determinants of erlotinib toxicity

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3080-3080 ◽  
Author(s):  
C. M. Rudin ◽  
A. A. Desai ◽  
L. Janisch ◽  
M. Carducci ◽  
T. Karrison ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Positive Association ◽  
Skin Toxicity ◽  
Response Assessment ◽  
Blood Collection ◽  
Strong Correlations ◽  
Ca Repeat ◽  
Egfr Expression ◽  
Intron 1 ◽  
Skin Biopsies

3080 Background: A strong but unexplained association between skin toxicity (rash) and survival from erlotinib therapy has been noted for patients with several epithelial malignancies. The correlation between rash and clinical benefit appears to extend across classes of epidermal growth factor receptor (EGFR)-targeted agents. Several hypothetical explanations for this association have been suggested including polymorphisms of the EGFR locus as well as PD and PK variability. Methods: We conducted this 80-subject prospective study in patients with lung (N=43), head and neck (N=9), and ovarian cancer (N=28) given erlotinib 150 mg daily to evaluate several of these hypotheses. Patients underwent toxicity monitoring, response assessment, skin biopsies pretreatment and after 28 days for immunohistochemical (IHC) analysis, as well as blood collection for PK analysis and evaluation of EGFR genetic polymorphisms reported to influence EGFR expression level. Results: 72/80 subjects are evaluable for toxicity. Response correlates with both worst grade diarrhea (p=0.003) and rash (p=0.044). Initial PK analysis suggests a positive association between d15 erlotinib trough level and both diarrhea (p=0.091) and rash (p=0.076). Controlling for d15 erlotinib level, EGFR intron 1 CA repeat length is also associated with rash (p=0.030). Polymorphisms in the EGFR promoter (216 G/T and 191 C/A) correlated with diarrhea (p=0.053 and 0.005 respectively) but not rash. IHC analyses including EGFR, p-EGFR, Akt, p-Akt, ERK, and p-ERK have been completed on 35 paired, pre-post treatment skin biopsies and demonstrate no strong correlations with toxicity. Conclusions: These data suggest that both interindividual PK variability and EGFR polymorphisms may contribute to erlotinib toxicity. Erlotinib effects on EGFR signaling in skin do not appear to correlate with toxicity. Samples obtained in this study are available for analysis of other candidate PG determinants of both toxicity and PK variability. [Table: see text]

Pharmacogenetic Profiling for Cetuximab Plus Irinotecan Therapy in Patients With Refractory Advanced Colorectal Cancer

2008 ◽  
Vol 26 (9) ◽  
pp. 1427-1434 ◽  
Author(s):  
Francesco Graziano ◽  
Annamaria Ruzzo ◽  
Fotios Loupakis ◽  
Emanuele Canestrari ◽  
Daniele Santini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Salvage Therapy ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Skin Toxicity ◽  
Egfr Expression ◽  
Intron 1 ◽  
Epidermal Growth

PurposeRegulation of epidermal growth factor receptor (EGFR) signaling pathways may play a relevant role in determining the activity of cetuximab therapy in patients with metastatic colorectal cancer (MCRC). We investigated possible associations between genetic variants and clinical outcomes of MCRC patients treated with cetuximab-irinotecan salvage therapy.Patients and MethodsPatients who underwent cetuximab-irinotecan salvage therapy after disease progression during or after first-line bolus/infusional fluorouracil, leucovorin, and oxaliplatin chemotherapy and a second-line irinotecan-based regimen were considered eligible for analysis of polymorphisms with putative influence on cetuximab-related pathways. Epidermal growth factor (EGF) 61A>G, EGF receptor (EGFR) 216G>T, EGFR 497G>A, EGFR intron-1 (CA)ndinucleotide short (S)/long (L) variant, cyclin-D1 870A>G, immunoglobulin-G fragment-C receptors RIIIa 158G>T, and RIIa 131G>A were studied for a possible association with overall survival (OS) as the primary end point. Additional analyses were addressed at possible associations among polymorphisms and EGFR expression, toxicity, and response.ResultsIn 110 assessable patients, significant association with favorable OS was observed for EGFR intron-1 S/S and EGF 61 G/G genotypes. In the multivariate model, EGFR intron-1 S/S and EGF 61 G/G genotypes showed a hazard ratio of 0.41 (95% CI, 0.21 to 0.78; P = .006) and 0.44 (95% CI, 0.23 to 0.84; P = .01), respectively. EGFR intron-1 S/S carriers showed more frequent G2-G3 skin toxicity (χ2test = 12.7; P = .001) and treatment response (χ2test = 9.45; P = .008) than EGFR intron-1 L/L carriers.ConclusionAlthough additional studies are required for confirmation, our findings could optimize the use of cetuximab in MCRC patients.

scholarly journals Modulation of EGFR Gene Transcription by a Polymorphic Repetitive Sequence – a Link between Genetics and Epigenetics

2000 ◽  
Vol 15 (1) ◽  
pp. 105-110 ◽  
Author(s):  
F. Gebhardt ◽  
H. BÜrger ◽  
B. Brandt
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Model Calculations ◽  
Ca Repeat ◽  
Egfr Gene ◽  
Egfr Expression ◽  
Epidermal Growth

The epidermal growth factor receptor (EGFR) plays a crucial role in growth, differentiation and motility of normal as well as tumor cells. The transduction of extracellular signals to the cytoplasm via the receptor not only depends on ligand binding, but is also determined by the receptor density on the cell surface. Therefore, with regard to cancer diagnosis and therapeutic approaches targeting EGFR it is important to know how the expression level of EGFR is controlled. We found that transcription activity declines with increasing numbers of CA dinucleotides of a highly polymorphic CA repeat in the first intron of the epidermal growth factor receptor gene. In vivo data from cultured cell lines support these findings, although other regulation mechanisms can compensate this effect. In addition, we showed that RNA elongation terminates at a site closely downstream of the simple sequence repeat (SSR) and that there are two separate major transcription start sites. Model calculations for the helical DNA conformation revealed a high bendability in the EGFR polymorphic region, especially if the CA stretch is extended. These data suggest that the CA-SSR can act like a joint, bringing the promoter in proximity to a putative repressor protein bound downstream of the CA-SSR. The data indicate that this polymorphism may be a marker for cancer, linking genetic and epigenetic risk factors. Furthermore, in breast cancer, heterozygous tumors with short CA-SSR showed an elevated EGFR-expression in contrast to tumours with longer CA-SSR. Tumours with loss of heterozygosity in intron 1 of egfr revealed an increased EGFR expression if the longer allele was lost. Moreover, decreased EGFR gene levels were significantly correlated with poor prognosis in breast cancer.

Dermatological toxicities of panitumumab in the treatment of patients with metastatic colorectal cancer (mCRC) from three clinical studies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14551-14551 ◽  
Author(s):  
D. A. Drelich ◽  
L. Rose ◽  
M. Ramirez ◽  
M. Jacobs ◽  
E. Mitchell
Keyword(s):  
African American ◽  
Clinical Studies ◽  
Human Monoclonal Antibody ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Growth Factor Receptor ◽  
Skin Toxicity ◽  
Metastatic Potential ◽  
Median Number ◽  
Egfr Expression

14551 Introduction: Epidermal growth factor receptor (EGFr) expression in CRC is associated with metastatic potential and poor prognosis. Panitumumab, a fully human monoclonal antibody against EGFr, was approved for the treatment of patients with refractory mCRC. The main side effects of panitumumab include dermatological manifestations that have been termed “rash”. However, classification of the dermatological manifestations has not been clearly described. Methods: We summarized the dermatological manifestations of 19 patients from 3 clinical studies investigating the the safety and efficacy of panitumumab monotherapy in mCRC in a single institution. Two of these studies were open lable, phase 2 in design which enrolled patients with documented disease progression (PD) during or after adequate doses of fluoropyrimidine, irinotecan, and oxaliplatin chemotherapy. In the other panitumumab was given in combination with irinotecan or oxaliplatin with bevacuzumab, 5FU, and leucovorin. Pts received panitumumab at 6mg/kg Q2W until PD or intolerability. Skin assessments were made q2w. Results: Five patients were men (26%) and 14 (73%) women; 12 were Caucasian (63%) and 7 (36%) African American. The median age was 53 (Range 38–80). Tumor response, disease control, and skin manifestations did not correlate with tumor EGFr levels as assessed by immunohisxtochemistry (Dako EGFR pharmDxtm). No enhancement of skin toxicity was observed when panitumumab was combined with chemotherapy. The median number of cycles received was 11 (Range 3–20). All pts experienced erythema; 17 macular/papular; 13 pustular; 18 acneiform rash; 15 pruritis; 3 honey crusting; 15 dry/flaking; 11 paronychia; 9 hirsuitism; 9 trichomegaly; and all 7 African American patients had significant hyperpigmentation. Photograph illustrations of each category and severity will be presented. Conclusion: Rash associated with panitumumab is common and can be classified according to the clinical dermatological manifestations; specific treatment strategies should be developed and evaluated accordingly. This is the first report of hirsuitism in women and hyperpigmentation in African Americans. [Table: see text]

Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: A phase II study of the Belgian Group of Digestive Oncology.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 245-245 ◽  
Author(s):  
I. Borbath ◽  
A. Ceratti ◽  
C. Verslype ◽  
A. Demols ◽  
T. Delaunoit ◽  
...  
Keyword(s):  
Skin Rash ◽  
Phase Ii ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Skin Toxicity ◽  
Standard Of Care ◽  
Egfr Expression ◽  
Prior Systemic Therapy ◽  
Ecog Ps

245 Background: Cholangiocarcinomas (CCK) are uncommon tumors with an increasing incidence and a poor prognosis. Epidermal growth factor receptor (EGFR) expression and activation in CCK have been demonstrated. Methods: We conducted a multicenter phase II trial combining cetuximab (Ctx), an anti-EGFR chimerized IgG1 monoclonal antibody, to gemcitabine (Gem). Patients with either locally advanced (LA) or metastatic (M) CCK (excluding gallbladder) were included; no prior systemic therapy was allowed. Ctx was administrated at the initial dose of 400 mg/m2 and further injections at 250 mg/m2 every 7 days, and Gem was administrated at 1000 mg/m2 on days 1, 8, and 15 every 4 weeks. The primary endpoint was the progression-free survival (PFS) rate at 6 months. A Simon 2-stage design was used. We hypothesized that Gem/Ctx would improve 6 month-PFS rate from 20% to 40%. We needed 3 patients with PFS ≥ 6 months from the first 13 to further include a total of 43 patients. Results: Forty-four patients with advanced CCK (41% LA/59%M) were enrolled from 09/2008 to 01/2010. Median age was 61.5 years (range 40-86) and baseline ECOG PS was 0 for 68% and 1 for 32% of the patients. Forty-three percent of the patients had prior surgery. Forty-six percent of the patients were free from progression at 6 months. Median PFS was 5.8 months (95% CI, 4.4-7.4 m) and median overall survival was 11.6 months (95% CI, 8.7-14.6 m). Nine patients (20.9%) had partial response with a median duration of 5 months (range 2-10 m). Disease control rate (PR + SD > 8 weeks) was 81.4%. The most common grades 3/4 related-toxicities were haematological abnormalities (47.7%), skin rash (13.6%) and fatigue (11.3%). Due to toxicity, 6 patients discontinued study treatment; 14 and 3 patients had a Gem and Ctx dose reduction respectively. Among the nine responders, 8 experienced a skin rash of at least grade 2, suggesting a relationship between skin toxicity and efficacy. Conclusions: Our study met its endpoint, i.e., a PFS rate of 46% at 6 months, suggesting that Gem-Ctx combination had promising activity with a manageable toxicity profile in advanced CCK. Adding Ctx to the new standard of care Gem-cisplatin deserves further investigations in CCK. [Table: see text]

Lack of association with epidermal growth factor receptor gene polymorphisms with clinical outcome in patients with advanced colorectal cancer treated with platinum-based chemotherapy

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3079-3079 ◽  
Author(s):  
D. J. Park ◽  
W. Zhang ◽  
M. Gordon ◽  
D. Y. Yang ◽  
R. Ladner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Advanced Colorectal Cancer ◽  
Receptor Gene ◽  
Growth Factor Receptor ◽  
Ca Repeat ◽  
Egfr Gene ◽  
Intron 1 ◽  
Platinum Based Chemotherapy

3079 Background: We had previously shown an association between functional polymorphisms of the epidermal growth factor receptor gene and clinical outcome to platinum-based chemotherapy in advanced colorectal cancer in a retrospective study. Specifically, patients with <20 CA repeats in intron-1 of the EGFR gene were shown to have increased risk of disease progression. Here in, we report our findings of a confirmatory prospective study. Methods: Between September 2001 and August 2004, 173 patients with advanced refractory colorectal cancer were enrolled. Patients received 5-FU 200 mg/m2/day as continuous infusion and oxaliplatin 130 mg/m2, in three week cycles. Blood samples for genomic analysis were available for 152 patients. EGFR intron 1 CA-repeat and HER1- R497K polymorphisms and their relationship with clinical response, time-to-progression, overall survival, and toxicity, either alone or in combination were assessed prospectively. In addition, we were able to perform quantitative gene expression analysis of EGFR through RT-PCR in a subset of 58 patients. Results: Our cohort of 152 patients comprised 78 males and 74 females, with a median age of 60. There were 105 Caucasians, 24 Asians, 5 Blacks, and 18 Hispanics. The median number of cycles received was 5. The median survival was 10.3 months with a median follow-up of 18.6 months. There were 28 responders (19%). Asians were more likely to possess longer CA repeats and the HER1- 497K variant (Fisher’s exact test p<0.05). Neither EGFR intron-1 CA repeat nor the HER1- R497K polymorphisms were associated with clinical response, time-to-progression, overall survival, toxicity (p>0.10). EGFR gene expression was not associated with clinical outcome (p>0.10). Shorter EGFR intron-1 CA repeats (<20) was associated with higher EGFR gene expression (Kruskal-Wallis t test p=0.013)Conclusion: We were not able to confirm prospectively a previously reported association between functional EGFR gene polymorphisms and clinical outcome to platinum-based therapy in patients with advanced colorectal cancer. In-vitro studies assessing differential oxaliplatin sensitivity with respect to EGFR expression are on-going. [Table: see text]

Cetuximab reversal of resistance to chronomodulated chemotherapy in heavily-pretreated patients with metastatic colorectal cancer (MCC) without amplification of epidermal growth factor receptor (EGFR) gene

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13104-13104
Author(s):  
F. A. Lévi ◽  
A. Karaboué ◽  
M. Bralet ◽  
P. Innominato ◽  
M. O. Herelle ◽  
...  
Keyword(s):  
Gene Amplification ◽  
Skin Rash ◽  
Growth Factor Receptor ◽  
Sensory Neuropathy ◽  
Skin Toxicity ◽  
Egfr Expression ◽  
Gene Copies ◽  
Heavily Pretreated ◽  
Or Gene ◽  
Peripheral Sensory

13104 Background Skin toxicity and EGFR amplification reportedly predicted for Cetux-reversal of MCC resistance to standard chemotherapy. We explored these relations for Cetux reversal of resistance to chronomodulated chemotherapy (Chrono) with irinotecan (CPT11, peak at 5 am), 5-fluorouracil-leucovorin (FU-LV, peak at 4 am) and oxaliplatin (l-OHP, peak at 4 pm). Methods: 40 pts with progressive MCC on 3 prior chemotherapy lines received weekly Cetux (250 mg/m2) and q2–3 wks CPT11-based (30 pts) or oxaliplatin-based (10 pts) Chrono. Toxicities and response were assessed q2–3 wks and q2 months (mo) respectively. Tumor EGFR expression was determined by immunohistochemistry for all pts and gene copies by fluorescent in situ hybridization (FISH) for 25 pts. Results: All pts had prior progression on CPT11, FU-LV and l-OHP. Median age: 61 yo; M/F: 24/16; WHO PS 0/1/2: 27/9/4; colon/rectum: 21/19; M sites 1/2/≥ 3: 12/15/13; liver/lung: 32/29; pre-existing peripheral sensory neuropathy grade ≥ 2: 11 pts. A median of 8 courses of Cetux-Chrono was given (1 to 22). Three pts withdrew for grade 4 allergy. 37 pts were assessable for other toxicities and 36 for response (1 too early). Gr 2–3 acneiform skin rash occurred in 27 pts (73%), with gr3 in 11 pts (29.7%). Other main gr 3–4 toxicities were diarrhea (27% of the pts), neutropenia (24.3%) and neuropathy (21.6%). Disease progressed in 12 pts (33.3%) and was controlled in 24 pts (66.7%) including 13 stable disease (36.1%) and 10 objective responses (8 PR and 2 CR) - 27.8% [95% C.L. 12.9 to 42.7]. EGFR was expressed in 32 pts (80%), with >10% + tumor cells for 14 pts (35%). 3/6 EGFR- pts (50%) and 7/32 EGFR+ pts (21.9%) responded. No gene amplification was documented in the 25 tumors (7 responders). A positive correlation between skin rash and disease control was suggested (p from χ2 = 0.08). Median progression free and overall survival (mo) are 5.3 [2.9–8.4] and 11.1 [8.6–13.6] respectively. Conclusions: Cetux partly alleviated MCC resistance to Chrono, independently of tumor EGFR protein expression or gene amplification, possibly through interfering with TGFα. This EGFR ligand carries poor prognosis for MCC and alters circadian clock function. [Table: see text]

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