Breast cancer survival predicted by TP53 mutation status differs markedly depending on treatment

Abstract

BackgroundPrevious studies on the role of TP53 mutation in breast cancer treatment response and survival are contradictory and inconclusive, limited by the use of different endpoints to determine clinical significance and by small sample sizes that prohibit stratification by treatment.MethodsWe utilized large datasets to examine overall survival according to TP53 mutation status in patients across multiple clinical features and treatments.ResultsConfirming other studies, we found that in all patients and in hormone therapy-treated patients, TP53 wild-type status conferred superior 5-year overall survival, but survival curves crossed at 10 or more years. In contrast, further stratification within the large dataset revealed that in patients receiving chemotherapy and no hormone therapy, wild-type TP53 status conferred remarkably poor overall survival. This previously unrecognized inferior survival is consistent with p53 inducing arrest/senescence instead of apoptosis. Addition of hormone therapy to chemotherapy improved survival notably in patients with TP53 wild-type tumors, but not mutant, suggesting hormone therapy could eradicate arrested/senescent cells. Testing this, we found that estrogen receptor-positive, TP53 wild-type breast cancer cells that were made senescent by doxorubicin treatment were sensitive to tamoxifen.ConclusionsThe poor survival of chemotherapy-treated patients with TP53 wild-type tumors may be improved by strategies to eliminate senescent cells, including the addition of hormone therapy when appropriate.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1044-5) contains supplementary material, which is available to authorized users.

Chemotherapy-induced senescent cancer cells engulf other cells to enhance their survival

“…Breast cancers are frequently wild type for TP53 (Shahbandi and Jackson, 2019), and compelling evidence from our laboratory and others shows that chemotherapy-treated breast cancers that are TP53 wild type are more likely to have residual disease (Bertheau et al, 2002, 2007; Chen et al, 2012; Esserman et al, 2012; Nakamura et al, 2012; Wang et al, 2016; Goetz et al, 2017), with senescent cells present (te Poele et al, 2002; Jackson et al, 2012; Tonnessen-Murray et al, 2018), resulting in markedly worse survival (Ungerleider et al, 2018). The present study reveals a previously unknown ability of chemotherapy-induced senescent cancer cells to engulf and degrade nearby cells, resulting in enhanced survival and providing compelling explanations for well-known but poorly understood senescent cell phenotypes such as SASP and SA-βGAL staining.…”

“…Engulfment by senescent cells increased their survival and could provide building blocks that might enable SASP to drive relapse. These factors suggest immediate clinical relevance, as p53-mediated induction of senescence contributes to poor response (Bertheau et al, 2002; Jackson et al, 2012) and poor survival (Ungerleider et al, 2018) of breast cancer patients.…”

Gas6 expression is reduced in advanced breast cancers

“…Luminal B and Her2 + subtypes generally have lower overall survival owing to their fast growth and tendency to relapse after removal. Likewise, basal-like breast cancer is associated with poor overall survival, partly due to increased metastatic potential and a lack of targeted therapeutic strategies 22,34,35 , although a proportion of these patients are associated with good prognosis 36 . These observations led us to ask whether Gas6 expression in human breast cancers correlates with overall survival.…”

HER2 Gene Amplification in ER-positive HER2 Immunohistochemistry 0 or 1+ Breast Cancer With Early Recurrence

“…The association between overexpression of p53 and poor prognosis has been reported in premenopausal breast cancer patients treated with tamoxifen after chemotherapy (16). A recent study has also demonstrated that TP53 wild-type status conferred superior 5-year overall survival in patients treated with adjuvant endocrine therapy (17). We previously reported that 20% of ER-positive breast cancer patients showed p53 accumulation by IHC (18), and that p53 accumulation predicted resistance to endocrine therapy and decreased post-relapse survival in metastatic breast cancer (19).…”