Prävalenz von PIK3CA-Genmutationen beim Mammakarzinom

Introduction:

The AKT/mTOR pathway is activated by phosphorylation of the lipid kinase phosphatidylinositol 3-kinase (PI3K) and regulates proliferation, apoptosis, survival and adhesion of tumor cells. In up to 30% of breast cancers, dysregulation of PI3K is reported, resulting from mutations in the PIK3CA gene that encodes the catalytic subunit (p110a). Hotspots of mutations were described in exon 9 (helical domain, E542K, G > A) and exon 20 (kinase domain, H1047R, A > G). Prevalence and the prognostic impact of the PIK3CA mutations as well as the predictive value with regard to endocrine therapy are controversially discussed. In this study we describe the prevalence of PIK3CA mutations in a consecutive cohort of breast cancer patients and its association to tumor characteristics and known prognostic factors.

Material & Methods:

Fresh frozen tumor samples were obtained from a consecutive cohort of 700 breast cancer patients (inclusion criteria: pTx pNx M0 Gx HRx HER2x) who were primarily operated in 6 centres between 2009 and 2011. Tumor DNA was extracted and analyzed by conventional and quantitative PCR (exon 9: cosmid 763 and exon 20: cosmid 775). Patient data, tumor characteristics and prognostic factors were obtained from patients charts. ER, PgR and HER2 results were based on local pathology, uPA and PAI-1 values were determined centrally.

Results:

All isolated DNA (n = 700) were analyzable by PCR and showed a mutation rate of 22% in the entire cohort; including two tumors with both mutations. Among the tumors with a positive steroid hormone receptor (HR) status (n = 606; 87%), we found a mutation rate of 24% for PIK3CA, whereas only 9 (10%) of 94 HR-negative tumors were mutated. Tumors with a PIK3CA mutation were significantly associated with HR positivity/HER2 negativity (p= 0,001). 14% of the cohort was HER2 positive. In 98 cases with a HER2 positive tumor 17 DNAs were mutated (17%) and 139 DNAs of the 602 HER2 negative tumors had a positive PIK3Ca mutation status (23%). Of the mutated tumors, 94% were HR positive, and 11% HER2 positive. Only three samples were HER2 positive and HR-negative. 6% of the mutated tumors were triple negative.

No significant association was found to age, menopausal status, tumor stage, nodal status, grading and uPA/PAI-1 status. Most mutant tumors were histological grade 2 (p = 0,001). A quarter of the intermediate risk group according to St. Gallen risk estimation had a somatic PIK3CA mutation.

Conclusion:

In our cohort, nearly all mutated tumors are hormone receptor positive and a minority of all mutated samples is HER2 positive. This data adds important information to the heterogeneous results of other previously published patient cohorts. It suggests a possible role of PI3K-dysregulation with regard to resistance against endocrine therapy and anti-HER2-treatment.