Epidermal growth factor receptor gene copy number, K-ras mutation and pathological response to preoperative cetuximab, 5-FU and radiation therapy in locally advanced rectal cancer

Carmelo Bengala, S. Bettelli, F. Bertolini, S. Salvi, S. Chiara, C. Sonaglio, L. Losi, N. Bigiani, G. Sartori, C. Dealis, N. Malavasi, R. D'Amico, G. Luppi, B. Gatteschi, A. Maiorana, P. F. Conte

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Abstract

Background: Cetuximab improves activity of chemotherapy in metastatic colorectal cancer (mCRC). Gene copy number (GCN) of epidermal growth factor receptor (EGFR) has been suggested to be a predictive factor of response to cetuximab in patients (pts) with mCRC; on the contrary, K-ras mutation has been associated with cetuximab resistance. Patients and methods: We have conducted a phase II study with cetuximab administered weekly for 3 weeks as single agent and then with 5-fluorouracil and radiation therapy as neo-adjuvant treatment for locally advanced rectal cancer (LARC). EGFR immunohistochemistry expression, EGFR GCN and K-ras mutation were evaluated on diagnostic tumor biopsy. Dworak's tumor regression grade (TRG) was evaluated on surgical specimens. Results: Forty pts have been treated; 39 pts are assessable. TRG 3 and 4 were achieved in nine (23.1%) and three pts (7.7%) respectively; TRG 3-4 rate was 55% and 5.3% in case of high and low GCN, respectively (P 0.0016). Pts with K-ras mutated tumors had lower rate of high TRG: 11% versus 36.7% (P 0.12). In pts with wild-type K-ras, TRG 3-4 rate was 58.8% versus 7.7% in case of high or low GCN, respectively (P 0.0012). Conclusions: In pts with LARC, EGFR GCN is predictive of high TRG to cetuximab plus 5-FU radiotherapy. Moreover, our data suggest that a wild-type K-ras associated with a high EGFR GCN can predict sensitivity to cetuximab-based treatment.

Original languageEnglish
Pages (from-to)469-474
Number of pages6
JournalAnnals of Oncology
Volume20
Issue number3
DOIs
Publication statusPublished - 2009

Fingerprint

erbB-1 Genes
Gene Dosage
Rectal Neoplasms
Fluorouracil
Radiotherapy
Mutation
Neoplasms
Epidermal Growth Factor Receptor
Colorectal Neoplasms
Cetuximab
Immunohistochemistry
Biopsy
Drug Therapy

Keywords

  • Cetuximab
  • EGFR
  • KRAS
  • Neoadjuvant chemo-radiotherapy
  • Rectal cancer

ASJC Scopus subject areas

  • Oncology
  • Hematology

Cite this

Epidermal growth factor receptor gene copy number, K-ras mutation and pathological response to preoperative cetuximab, 5-FU and radiation therapy in locally advanced rectal cancer. / Bengala, Carmelo; Bettelli, S.; Bertolini, F.; Salvi, S.; Chiara, S.; Sonaglio, C.; Losi, L.; Bigiani, N.; Sartori, G.; Dealis, C.; Malavasi, N.; D'Amico, R.; Luppi, G.; Gatteschi, B.; Maiorana, A.; Conte, P. F.

In: Annals of Oncology, Vol. 20, No. 3, 2009, p. 469-474.

Research output: Contribution to journalArticle

Bengala, C, Bettelli, S, Bertolini, F, Salvi, S, Chiara, S, Sonaglio, C, Losi, L, Bigiani, N, Sartori, G, Dealis, C, Malavasi, N, D'Amico, R, Luppi, G, Gatteschi, B, Maiorana, A & Conte, PF 2009, 'Epidermal growth factor receptor gene copy number, K-ras mutation and pathological response to preoperative cetuximab, 5-FU and radiation therapy in locally advanced rectal cancer', Annals of Oncology, vol. 20, no. 3, pp. 469-474. https://doi.org/10.1093/annonc/mdn647
Bengala, Carmelo ; Bettelli, S. ; Bertolini, F. ; Salvi, S. ; Chiara, S. ; Sonaglio, C. ; Losi, L. ; Bigiani, N. ; Sartori, G. ; Dealis, C. ; Malavasi, N. ; D'Amico, R. ; Luppi, G. ; Gatteschi, B. ; Maiorana, A. ; Conte, P. F. / Epidermal growth factor receptor gene copy number, K-ras mutation and pathological response to preoperative cetuximab, 5-FU and radiation therapy in locally advanced rectal cancer. In: Annals of Oncology. 2009 ; Vol. 20, No. 3. pp. 469-474.
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abstract = "Background: Cetuximab improves activity of chemotherapy in metastatic colorectal cancer (mCRC). Gene copy number (GCN) of epidermal growth factor receptor (EGFR) has been suggested to be a predictive factor of response to cetuximab in patients (pts) with mCRC; on the contrary, K-ras mutation has been associated with cetuximab resistance. Patients and methods: We have conducted a phase II study with cetuximab administered weekly for 3 weeks as single agent and then with 5-fluorouracil and radiation therapy as neo-adjuvant treatment for locally advanced rectal cancer (LARC). EGFR immunohistochemistry expression, EGFR GCN and K-ras mutation were evaluated on diagnostic tumor biopsy. Dworak's tumor regression grade (TRG) was evaluated on surgical specimens. Results: Forty pts have been treated; 39 pts are assessable. TRG 3 and 4 were achieved in nine (23.1{\%}) and three pts (7.7{\%}) respectively; TRG 3-4 rate was 55{\%} and 5.3{\%} in case of high and low GCN, respectively (P 0.0016). Pts with K-ras mutated tumors had lower rate of high TRG: 11{\%} versus 36.7{\%} (P 0.12). In pts with wild-type K-ras, TRG 3-4 rate was 58.8{\%} versus 7.7{\%} in case of high or low GCN, respectively (P 0.0012). Conclusions: In pts with LARC, EGFR GCN is predictive of high TRG to cetuximab plus 5-FU radiotherapy. Moreover, our data suggest that a wild-type K-ras associated with a high EGFR GCN can predict sensitivity to cetuximab-based treatment.",
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author = "Carmelo Bengala and S. Bettelli and F. Bertolini and S. Salvi and S. Chiara and C. Sonaglio and L. Losi and N. Bigiani and G. Sartori and C. Dealis and N. Malavasi and R. D'Amico and G. Luppi and B. Gatteschi and A. Maiorana and Conte, {P. F.}",
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T1 - Epidermal growth factor receptor gene copy number, K-ras mutation and pathological response to preoperative cetuximab, 5-FU and radiation therapy in locally advanced rectal cancer

AU - Bengala, Carmelo

AU - Bettelli, S.

AU - Bertolini, F.

AU - Salvi, S.

AU - Chiara, S.

AU - Sonaglio, C.

AU - Losi, L.

AU - Bigiani, N.

AU - Sartori, G.

AU - Dealis, C.

AU - Malavasi, N.

AU - D'Amico, R.

AU - Luppi, G.

AU - Gatteschi, B.

AU - Maiorana, A.

AU - Conte, P. F.

PY - 2009

Y1 - 2009

N2 - Background: Cetuximab improves activity of chemotherapy in metastatic colorectal cancer (mCRC). Gene copy number (GCN) of epidermal growth factor receptor (EGFR) has been suggested to be a predictive factor of response to cetuximab in patients (pts) with mCRC; on the contrary, K-ras mutation has been associated with cetuximab resistance. Patients and methods: We have conducted a phase II study with cetuximab administered weekly for 3 weeks as single agent and then with 5-fluorouracil and radiation therapy as neo-adjuvant treatment for locally advanced rectal cancer (LARC). EGFR immunohistochemistry expression, EGFR GCN and K-ras mutation were evaluated on diagnostic tumor biopsy. Dworak's tumor regression grade (TRG) was evaluated on surgical specimens. Results: Forty pts have been treated; 39 pts are assessable. TRG 3 and 4 were achieved in nine (23.1%) and three pts (7.7%) respectively; TRG 3-4 rate was 55% and 5.3% in case of high and low GCN, respectively (P 0.0016). Pts with K-ras mutated tumors had lower rate of high TRG: 11% versus 36.7% (P 0.12). In pts with wild-type K-ras, TRG 3-4 rate was 58.8% versus 7.7% in case of high or low GCN, respectively (P 0.0012). Conclusions: In pts with LARC, EGFR GCN is predictive of high TRG to cetuximab plus 5-FU radiotherapy. Moreover, our data suggest that a wild-type K-ras associated with a high EGFR GCN can predict sensitivity to cetuximab-based treatment.

AB - Background: Cetuximab improves activity of chemotherapy in metastatic colorectal cancer (mCRC). Gene copy number (GCN) of epidermal growth factor receptor (EGFR) has been suggested to be a predictive factor of response to cetuximab in patients (pts) with mCRC; on the contrary, K-ras mutation has been associated with cetuximab resistance. Patients and methods: We have conducted a phase II study with cetuximab administered weekly for 3 weeks as single agent and then with 5-fluorouracil and radiation therapy as neo-adjuvant treatment for locally advanced rectal cancer (LARC). EGFR immunohistochemistry expression, EGFR GCN and K-ras mutation were evaluated on diagnostic tumor biopsy. Dworak's tumor regression grade (TRG) was evaluated on surgical specimens. Results: Forty pts have been treated; 39 pts are assessable. TRG 3 and 4 were achieved in nine (23.1%) and three pts (7.7%) respectively; TRG 3-4 rate was 55% and 5.3% in case of high and low GCN, respectively (P 0.0016). Pts with K-ras mutated tumors had lower rate of high TRG: 11% versus 36.7% (P 0.12). In pts with wild-type K-ras, TRG 3-4 rate was 58.8% versus 7.7% in case of high or low GCN, respectively (P 0.0012). Conclusions: In pts with LARC, EGFR GCN is predictive of high TRG to cetuximab plus 5-FU radiotherapy. Moreover, our data suggest that a wild-type K-ras associated with a high EGFR GCN can predict sensitivity to cetuximab-based treatment.

KW - Cetuximab

KW - EGFR

KW - KRAS

KW - Neoadjuvant chemo-radiotherapy

KW - Rectal cancer

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DO - 10.1093/annonc/mdn647

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