46Pp53 mutations in HER2 positive and triple negative breast cancer treated with neoadjuvant chemotherapy – A translational subproject of the GeparSixto trial

p53 is among the most frequently mutated genes in breast cancer. However, its predictive value as to chemotherapy response has not been sufficiently determined to date. The CALGB 40601 study showed a positive impact of p53 status on response to neoadjuvant therapy with anthracyclines, taxanes and anti-HER2 agents in 185 HER+ breast cancers. Sanger sequencing was performed in 450 pre-therapeutic triple-negative (TNBC, n = 346, 54.7%) and HER2+ (n = 204, 45.3%) breast cancer core biopsies of the neoadjuvant phase II GeparSixto clinical trial (GBG 66; NCT01426880) to cover the DNA-binding domain of p53 in exons 5 to 8. Mutations were classified according to mutation effect, transactivation class, effect on protein sequence, residue function, and predicted gain of function. Patients received weekly liposomal doxorubicin, paclitaxel w/o carboplatin, bevacizumab (only TNBC), trastuzumab and lapatinib (only HER2+ tumors). p53 mutations were found in 66.0% of the total study group and were evenly distributed between exons 5 to 8 (22.6-26.6%). TNBC were significantly more frequently mutated than HER2+ tumors (74.8% vs. 55.4%, p < 0.0001). p53 mutated tumors also revealed significantly higher ki67 indices (p = 0.003). No associations were seen between p53 status and pathological complete response (pCR, ypT0 ypN0; pCR rate 38.0% vs. 37.9%, OR = 1.01, 95% CI = 0.67-1.50 p = 0.977). Furthermore, no associations were seen within the groups of TNBC and HER2+ tumors, particularly with pCR (pCR rate in TNBC mt vs. wt 56.5% vs. 58.1%; pCR rate in HER+ mt vs. wt 70.8% vs. 64.8%), clinico-pathological factors, ki67 index, immunological parameters, PIK3CA mutations (p > 0.05). p53 mutations are prevalent in a high proportion of triple-negative and HER2+ breast cancers. In contrast to the CALGB 40601 study we could not observe a correlation between p53 mutations and pCR after a comparable neoadjuvant chemotherapy.Disclosure: All authors have declared no conflicts of interest. p53 is among the most frequently mutated genes in breast cancer. However, its predictive value as to chemotherapy response has not been sufficiently determined to date. The CALGB 40601 study showed a positive impact of p53 status on response to neoadjuvant therapy with anthracyclines, taxanes and anti-HER2 agents in 185 HER+ breast cancers. Sanger sequencing was performed in 450 pre-therapeutic triple-negative (TNBC, n = 346, 54.7%) and HER2+ (n = 204, 45.3%) breast cancer core biopsies of the neoadjuvant phase II GeparSixto clinical trial (GBG 66; NCT01426880) to cover the DNA-binding domain of p53 in exons 5 to 8. Mutations were classified according to mutation effect, transactivation class, effect on protein sequence, residue function, and predicted gain of function. Patients received weekly liposomal doxorubicin, paclitaxel w/o carboplatin, bevacizumab (only TNBC), trastuzumab and lapatinib (only HER2+ tumors). p53 mutations were found in 66.0% of the total study group and were evenly distributed between exons 5 to 8 (22.6-26.6%). TNBC were significantly more frequently mutated than HER2+ tumors (74.8% vs. 55.4%, p < 0.0001). p53 mutated tumors also revealed significantly higher ki67 indices (p = 0.003). No associations were seen between p53 status and pathological complete response (pCR, ypT0 ypN0; pCR rate 38.0% vs. 37.9%, OR = 1.01, 95% CI = 0.67-1.50 p = 0.977). Furthermore, no associations were seen within the groups of TNBC and HER2+ tumors, particularly with pCR (pCR rate in TNBC mt vs. wt 56.5% vs. 58.1%; pCR rate in HER+ mt vs. wt 70.8% vs. 64.8%), clinico-pathological factors, ki67 index, immunological parameters, PIK3CA mutations (p > 0.05). p53 mutations are prevalent in a high proportion of triple-negative and HER2+ breast cancers. In contrast to the CALGB 40601 study we could not observe a correlation between p53 mutations and pCR after a comparable neoadjuvant chemotherapy. Disclosure: All authors have declared no conflicts of interest.