Survival Outcomes by TP53 Mutation Status in Metastatic Breast Cancer

Abstract

Purpose: We sought to determine the significant genomic alterations in patients with metastatic breast cancer (MBC), and survival outcomes in common genotypes. Patients and Methods: High-depth next generation sequencing was performed for 202 genes in tumor and normal DNA from 257 patients with MBC, including 165 patients with ER/PR+ HER2- (hormone receptor positive, HR+ positive), 32 patients with HER2+ and 60 patients with triple negative (ER/PR/HER2-) cancer. Kaplan Meier survival analysis was performed in our discovery set, in breast cancer patients analyzed in The Cancer Genome Atlas, and in a separate cohort of 98 patients with MBC who underwent clinical genomic testing. Results: Significantly mutated genes (SMGs) varied by histology and tumor subtype, but TP53 was a SMG in all three subtypes. The most SMGs in HR+ patients included PIK3CA (32%), TP53 (29%), GATA3 (15%), CDH1 (8%), MAP3K1 (8%), PTEN (5%), TGFBR2 (4%), AKT1 (4%), and MAP2K4 (4%). TP53 mutations were associated with shorter recurrence-free survival (P=0.004), progression-free survival (P=0.00057) and overall survival (P=0.003). Further, TP53 status was prognostic among HR+ patients with PIK3CA mutations. TP53 mutations were also associated with poorer overall survival in the 442 HR+ breast cancer patients in the TCGA (P=0.042) and in an independent set of 96 HR+ MBC who underwent clinical sequencing (P=0.0004). Conclusions: SMGs differ by tumor subtype but TP53 is significantly mutated in all three breast cancer subtypes. TP53 mutations are associated with poor prognosis in HR+ breast cancer. TP53 mutations should be considered in the design and interpretation of precision oncology trials.

Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients withAKT1E17K-Mutant, ER-Positive Metastatic Breast Cancer

“…In this limited sample set, no obvious pattern in AKT1 E17K clonality or co-incident tumor mutations was associated with clinical outcome, although, potentially of interest, 6 of the 8 (75%) cases identified as low shedders by NGS had an objective response, and none of the patients whose tumors harbored a TP53 mutation achieved an objective response. While the sample size was small, the observed higher frequency of TP53 mutations in the fulvestrant-naïve compared with the fulvestrant-pretreated cohort (33% vs 12%, respectively) potentially supports the observation that this group had more aggressive disease biology (42). Equally, the identified TP53 mutations could be related to the greater degree of cytotoxic chemotherapy exposure in this cohort (43, 44).…”

The molecular landscape of Asian breast cancers reveals clinically relevant population-specific differences

“…However, unlike liver cancer where TP53 mutations may be linked to population-specific risk factors 51 , we found no difference in the type or location of mutations nor in mutational signatures in Asian and Caucasian breast tumours, suggesting that the source of mutations may be similar in both populations. Regardless of the cause of the mutations, TP53 mutations have been suggested to be prognostic, but with opposite effects in different subtypes of breast cancer 52,53 , and in ER+ /HER2− disease, TP53 mutations appear to be associated with higher risk to recurrence and poorer prognosis [54][55][56] . Notably, expression of TP53 mutations may have different effects in different populations 57 , highlighting the need for further clinical studies in diverse populations.…”

Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer

“…Although efficacy appeared marginally better in fulvestrantpretreated than in fulvestrant-naive patients, there were notable phenotypic and genomic differences between these patient cohorts. Specifically, at enrollment, fulvestrant-naive patients had more visceral disease, received less prior endocrine and more chemotherapy, and, likely reflective of this prior therapy receipt, had a lower ESR1-and higher TP53-mutation rate, which indeed could also be indicative of a more aggressive disease biology at baseline 21 . Overall, however, and given the poor prognostic genomic subgroup selected for this study, reasonable efficacy (ORR 21%; CBR 24 42%) was seen in the fulvestrant-pretreated cohort.…”