A personalised medicine resource
Bowel cancer is the second deadliest cancer in Australia.
However, with the arrival of more chemotherapy options and with the availability of biologic therapies in the recent past, mortality rates are declining, and patients are living longer.
Over the past 20 years, survival in metastatic bowel cancer has more than doubled.
The main histologic subtype of bowel cancer is adenocarcinoma.
Bowel adenocarcinomas arise through a series of mutations that occur over the space of many years, and results in the evolution of normal tissue to adenoma to carcinoma to metastasis.
In the past two decades, there has been increasing recognition that some mutations may be prognostic or predictive markers for specific therapies available in bowel cancer.
These mutations involve genes such as KRAS, BRAF, PIK3CA, AKT1, SMAD4, PTEN, NRAS, and TGFBR2.
Knowledge of the genetic mutations associated with different cancer types is increasing rapidly and is already influencing treatment choices.
The My Cancer Genome website is a database of information on genes, genetic mutations and cancer. It includes information on the latest research and the latest treatments across many cancer types (including bowel cancer).
The website also highlights the benefits of genetic testing especially when knowledge of a particular gene mutation can affect treatment decisions.
For example, RAS testing in bowel cancer patients can help decide whether they are likely to respond to specific targeted therapies such as Erbitux (cetuximab) or Vectibix (panitumumab).
Mutations in other genes such as BRAF, PIK3CA, AKT1, SMAD4, PTEN, NRAS, and TGFBR2F are also relevant for bowel cancer patients and their families.
Approximately 36-40% of patients with bowel cancer have tumor-associated KRAS mutations.
Multiple studies have now shown that patients with tumors harboring mutations in KRAS are unlikely to benefit from anti-EGFR antibody therapy, either as monotherapy or in combination with chemotherapy.
Further, in trials of oxaliplatin based chemotherapy, the patients with KRAS mutated tumors appeared to do worse when treated with EGFR antibody therapy combined with an oxaliplatin based chemotherapy compared to the patients treated with an oxaliplatin based treatment alone.
Approximately 8-15% of bowel cancer tumors harbor BRAF mutations.
The presence of BRAF mutation is significantly associated with right-sided bowel cancers and is associated with decreased overall survival.
Several studies have reported that patients with metastatic bowel cancer that harbor BRAF mutations do not respond to anti-EGFR antibody agents cetuximab or panitumumab. Based on these findings, BRAF mutations were suggested to be a negative predictor of response to anti-EGFR therapy.
Mutations in AKT1 have been found in less than 1-6% of all bowel cancers.
In bowel cancer, the only AKT1 mutation observed up to this time is the E17K mutation, which has also been observed in other types of cancer.
Preclinical data have shown that the presence of this activating mutation results in cellular transformation in vitro and in vivo. Specific clinical characteristics of bowel cancer patients harboring AKT1 mutations have yet to be described.
Mutations in PIK3CA have been found in 10–30% of bowel cancers.
These mutations usually occur within two 'hotspot' areas within exon 9 (the helical domain) and exon 20 (the kinase domain).
PTEN mutations occur in 5-14% of bowel cancers. PTEN is a tumor suppressor gene, and loss of PTEN results in upregulation of the PI3K/ AKT pathway. PTEN loss of expression is observed with KRAS, BRAF, and PIK3CA mutations.
Germline mutations in PTEN result in PTEN hamartoma tumor syndrome and are associated with increased risk for melanoma, breast, thyroid, endometrial, colorectal, and kidney cancer report that PTEN mutations are weakly prognostic in stage IV bowel cancer patients. Research into the prognostic and predictive significance of PTEN mutations and other mechanisms for loss of PTEN expression is ongoing.
In retrospective studies, PTEN loss is associated with decreased sensitivity of bowel cancer tumors to anti-EGFR antibodies. PTEN loss is associated with lack of benefit of the anti-EGFR antibody, cetuximab.
SMAD4 mutations are found in approximately10–35% of bowel cancer tumors.
In bowel cancer, loss of SMAD4 has been historically thought to be a late event in tumor development with rates of SMAD4 loss of 0%, 8%, 6%, and 22% in stages I-IV bowel cancer, respectively. However, downregulation of SMAD4 is associated with worse survival in stages I–II bowel cancer patients. Loss of SMAD4 protein expression evaluated by immunohistochemistry in stage III (lymph node positive disease) is associated with worse overall and disease-free survival. Low SMAD4 expression may also identify a subset of patients with early recurrence after curative therapy.
SMAD4 mutations or loss of expression may portend a worse prognosis in patients with resected bowel cancer.