TP53 mutations and protein immunopositivity may predict for poor outcome but also for trastuzumab benefit in patients with early breast cancer treated in the adjuvant setting

George Fountzilas, Eleni Giannoulatou, Zoi Alexopoulou, Flora Zagouri, Eleni Timotheadou, Kyriaki Papadopoulou, Sotiris Lakis, Mattheos Bobos, Christos Poulios, Maria Sotiropoulou, Aggeliki Lyberopoulou, Helen Gogas, George Pentheroudakis, Dimitrios Pectasides, Angelos Koutras, Christos Christodoulou, Christos Papandreou, Epaminontas Samantas, Pavlos Papakostas, Paris Kosmidis, Dimitrios Bafaloukos, Charisios Karanikiotis, Meletios-Athanassios Dimopoulos, Vassiliki Kotoula, George Fountzilas, Eleni Giannoulatou, Zoi Alexopoulou, Flora Zagouri, Eleni Timotheadou, Kyriaki Papadopoulou, Sotiris Lakis, Mattheos Bobos, Christos Poulios, Maria Sotiropoulou, Aggeliki Lyberopoulou, Helen Gogas, George Pentheroudakis, Dimitrios Pectasides, Angelos Koutras, Christos Christodoulou, Christos Papandreou, Epaminontas Samantas, Pavlos Papakostas, Paris Kosmidis, Dimitrios Bafaloukos, Charisios Karanikiotis, Meletios-Athanassios Dimopoulos, Vassiliki Kotoula

Abstract

Background: We investigated the impact of PIK3CA and TP53 mutations and p53 protein status on the outcome of patients who had been treated with adjuvant anthracycline-taxane chemotherapy within clinical trials in the pre- and post-trastuzumab era.

Results: TP53 and PIK3CA mutations were found in 380 (21.5%) and 458 (25.9%) cases, respectively, including 104 (5.9%) co-mutated tumors; p53 immunopositivity was observed in 848 tumors (53.5%). TP53 mutations (p < 0.001) and p53 protein positivity (p = 0.001) were more frequent in HER2-positive and triple negative (TNBC) tumors, while PIK3CA mutations were more frequent in Luminal A/B tumors (p < 0.001). TP53 mutation status and p53 protein expression but not PIK3CA mutation status interacted with trastuzumab treatment for disease-free survival; patients with tumors bearing TP53 mutations or immunopositive for p53 protein fared better when treated with trastuzumab, while among patients treated with trastuzumab those with the above characteristics fared best (interaction p = 0.017 for mutations; p = 0.015 for IHC). Upon multivariate analysis the above interactions remained significant in HER2-positive patients; in the entire cohort, TP53 mutations were unfavorable in patients with Luminal A/B (p = 0.003) and TNBC (p = 0.025); p53 immunopositivity was strongly favorable in patients treated with trastuzumab (p = 0.009).

Materials and methods: TP53 and PIK3CA mutation status was examined in 1766 paraffin tumor DNA samples with informative semiconductor sequencing results. Among these, 1585 cases were also informative for p53 protein status assessed by immunohistochemistry (IHC; 10% positivity cut-off).

Conclusions: TP53 mutations confer unfavorable prognosis in patients with Luminal A/B and TNBC tumors, while p53 immunopositivity may predict for trastuzumab benefit in the adjuvant setting.

Keywords: PIK3CA mutations; TP53 mutations; early breast cancer; p53 immunohistochemistry; trastuzumab.

Conflict of interest statement

None.

Figures

Figure 1. Distribution of TP53 and PIK3CA…
Figure 1. Distribution of TP53 and PIK3CA mutations in early breast cancer
(A) TP53 mutations were dispersed throughout the coding region but aggregated in the area coding for the DNA binding domain of the protein. (B) PIK3CA mutations were more common in the kinase domain. In the pies in A and B, the distribution of mutation types per gene is shown. fs: frameshift; indels: insertions/deletions.
Figure 2. TP53 and PIK3CA mutation characteristics…
Figure 2. TP53 and PIK3CA mutation characteristics according to tumor subtypes
Mutations are described for presence / absence and domain specificity as indicated. TP53 mutations are compared for mutation types (missense, frameshift indels, nonsense). Y-axes have been truncated at 50%. Numbers per category are shown. Grey parts in bars: complementary to the colored category. All mutations and their characteristics were related to ER/PgR status. Helical, kinase: mutations in the corresponding domains of PIK3CA; fs-indels: frameshift insertions / deletions; TAD, oligo: TP53 transactivation and oligomerization domains.
Figure 3. TP53 and PIK3CA mutation effects…
Figure 3. TP53 and PIK3CA mutation effects on early breast cancer patient DFS according to main disease subtypes and trastuzumab treatment
The presence of TP53 mutations was unfavorable in Luminal A/B (A) and TNBC (B), indifferent in HER2-positive patients who were treated with anthracyclines only in the pre-trastuzumab era (C), but favorable in trastuzumab treated HER2-positive patients (D). (E) and (F): PIK3CA mutations in HER2-positive, non-trastuzumab and trastuzumab treated patients were similar to those described for TP53 mutations in (C) and (D), respectively.
Figure 4. TP53 mutations predictive for trastuzumab…
Figure 4. TP53 mutations predictive for trastuzumab benefit
Interactions between TP53 mutations and trastuzumab (A), and between p53 protein expression and trastuzumab (B) are shown. Trastuzumab (T) treated patients with TP53 mutations (A) or p53 positive protein expression by IHC (B) fared best; patients with the same TP53 tumor properties, who were not treated with trastuzumab, fared worst.
Figure 5. Forest plots for multivariable analyses…
Figure 5. Forest plots for multivariable analyses in the entire cohort
TP53 mutations and p53 protein expression were included in all models. p53 IHC positivity was unfavorable in HER2-positive patients not treated but favorable in those treated with trastuzumab.
Figure 6. REMARK chart
Figure 6. REMARK chart
All samples examined in this study have yielded informative NGS results. Immunohistochemistry (IHC) for p53 protein expression was applied on available tissues in the majority of the NGS informative samples.

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