Activity of temozolomide in patients with advanced chemorefractory colorectal cancer and MGMT promoter methylation

Blockade of the epidermal growth factor receptor (EGFR) with the monoclonal antibodies cetuximab or panitumumab is effective in a subset of colorectal cancers (CRCs), but the emergence of resistance limits the efficacy of these therapeutic agents. At relapse, the majority of patients develop RAS mutations, while a subset acquires EGFR extracellular domain (ECD) mutations. Here we find that patients who experience greater and longer responses to EGFR blockade preferentially develop EGFR ECD mutations, while RAS mutations emerge more frequently in patients with smaller tumour shrinkage and shorter progression-free survival. In circulating cell-free tumour DNA of patients treated with anti-EGFR antibodies, RAS mutations emerge earlier than EGFR ECD variants. Subclonal RAS but not EGFR ECD mutations are present in CRC samples obtained before exposure to EGFR blockade. These data indicate that clonal evolution of drug-resistant cells is associated with the clinical outcome of CRC patients treated with anti-EGFR antibodies.

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“…UP032). Ospedale Niguarda and IRCCS Istituto Nazionale dei Tumori used Sanger Sequencing according to the protocol described in refs 38, 39.…”

Section: Methodsmentioning

confidence: 99%

Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer

Emburgh¹,

Arena²,

Siravegna³

et al. 2016

Nat Commun

185

158

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“…Similar to colorectal cancer, we found that MGMT methylation is associated with KRAS mutation; it may be involved in the early steps of carcinogenesis through a defective DNA repair mechanism and an increase in the mutational rate of target genes such as KRAS itself. Moreover, MGMT methylation is associated with benefit from alkylating agents such as temozolomide in several cancers, including glioblastoma and colorectal cancer [14,33]. Recently, the combination of capecitabine and temozolomide was shown to be highly active in patients with well-to moderately differentiated neuroendocrine carcinomas [34], which are characterized by slow growing rates, similar to PPM.…”

Section: Discussionmentioning

confidence: 99%

“…The Oncologist ® for methylated and unmethylated templates, as described previously [13,14]. Two templates provided by the Methylation KIT were used as positive controls for methylated and unmethylated reactions.…”

Section: Biomarker Evaluationmentioning

confidence: 99%

FOLFOX-4 Chemotherapy for Patients With Unresectable or Relapsed Peritoneal Pseudomyxoma

et al. 2014

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Purpose. The standard treatment of peritoneal pseudomyxoma is based on cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC). The establishment of newer systemic treatments is an unmet clinical need for unresectable or relapsed peritoneal pseudomyxoma. The aim of our study was to assess the activity of chemotherapy with 5‐fluorouracil and oxaliplatin (FOLFOX‐4 regimen) in terms of response rate in this subset of patients. Materials and Methods. Patients were included in a single‐center, observational study and treated with FOLFOX‐4 administered every 2 weeks for up to 12 cycles or until progressive disease or unacceptable toxicity. Results. Twenty consecutive patients were reviewed from July 2011 to September 2013. Only partial responses were observed, with an objective response rate of 20%. Median progression‐free survival and overall survival were 8 months and 26 months, respectively. Two patients were able to undergo laparotomy with complete cytoreduction and HIPEC in one case. Safety data for FOLFOX‐4 were consistent with the literature. By means of a mutant enriched polymerase chain reaction, KRAS mutation was found in 16 of 19 cases (84%), and MGMT promoter methylation was found in 8 (42%, all KRAS mutant). Conclusion. FOLFOX‐4 chemotherapy is tolerable and active in patients with peritoneal pseudomyxoma when disease is deemed unresectable or relapsed after peritonectomy and HIPEC. The identification of predictive biomarkers, such as KRAS for resistance to anti‐epidermal growth factor receptor monoclonal antibodies and MGMT for response to temozolomide, is a priority for the development of evidence‐based treatment strategies for peritoneal pseudomyxoma.

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“…One study suggested that MGMT status could be a predictive factor of low recurrence in patients with curatively resected colorectal cancer (26). In addition, a recently published phase II study showed that temozolomide could serve as an additional treatment option in patients with advanced chemorefractory colorectal cancer having MGMT promotor methylation (27).…”

Section: Introductionmentioning

confidence: 99%

Phase 1 Study of Preoperative Chemoradiation Therapy With Temozolomide and Capecitabine in Patients With Locally Advanced Rectal Cancer

Jeong

Hong

Park

et al. 2016

International Journal of Radiation Oncology*Biology*Physics

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Activity of temozolomide in patients with advanced chemorefractory colorectal cancer and MGMT promoter methylation

Cited by 73 publications

References 23 publications

Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer

Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer

FOLFOX-4 Chemotherapy for Patients With Unresectable or Relapsed Peritoneal Pseudomyxoma

Phase 1 Study of Preoperative Chemoradiation Therapy With Temozolomide and Capecitabine in Patients With Locally Advanced Rectal Cancer

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