2. Department of Clinical Pathology, Odense University Hospital, Odense, Denmark.
3. Department of Clinical Genetics, Vejle-Lillebaelt Hospital, Denmark.
4. Department of Oncology, Vejle-Lillebaelt Hospital, Denmark.
5. Research Unit of General Practice Odense, Institute of Public Health, University of Southern Denmark, Denmark.
6. Institute of Regional Health Research, University of Southern Denmark, Denmark.
Background: HER-2 is a prognostic and predictive factor in patients suffering from breast cancer. Since 2006 we have tested routinely the HER-2 status in patients with primary breast cancer at Vejle Hospital, Denmark, to evaluate the indication for treatment with trastuzumab in the adjuvant setting. Although this treatment improves the prognosis in patients with HER-2 positive breast tumours, it seems that some patients do not respond to the treatment. Various molecular genetic pathways may be responsible for such resistance to trastuzumab therapy, e.g., mutations in the PIK3CA-gene. Mutation in the K-RAS-gene has critical impact in selecting patients with colorectal cancer for targeted anti-EGFR treatment, but has only been sparsely investigated in patients with breast cancer. It is the purpose of the present study to evaluate, whether such mutations may influence the response to trastuzumab treatment.
Methods: Paraffin-embedded breast cancer tissue from 69 women, treated according to protocol with trastuzumab in an adjuvant setting from 2006 through 2008, and 16 women, also treated with trastuzumab in an individualized setting from 2003 through 2005 were included, and analyzed for somatic mutation of the K-RAS, BRAF and PIK3CA genes in their breast tumours. The results were compared with clinical behaviour, receptor status, tumour grade, size, and lymph node status.
Results: In the 2006-08 material, PIK3CA mutations were detected in 26% of the tumours, whereas no BRAF or K-RAS mutations were found. In the 2003-05 material we documented PIK3CA mutations in 31%, BRAF in 6% (1 tumour), and K-RAS in none of the tumours. All patients experiencing relapse (N=17) had metastatic disease. No statistically significant associations were detected between PIK3CA mutation status and the clinico-pathological variables or the clinical outcome.
Conclusions: K-RAS and BRAF mutations are rare events in breast cancer, whereas PIK3CA-mutation is encountered in more than one fourth of HER-2 positive breast cancers, but seems without predictive impact regarding treatment response to trastuzumab in the investigated series of patients.
Keywords: Breast cancer, BRAF, HER-2, K-RAS, PIK3CA, treatment failure