TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer

Abstract

Background Whereas the genomic landscape of endocrine‐resistant breast cancer has been intensely characterized in previously treated cases with local or distant recurrence, comparably little is known about genomic alterations conveying primary non‐responsiveness to endocrine treatment in luminal early breast cancer. Methods In this study, 622 estrogen receptor‐expressing breast cancer cases treated with short‐term preoperative endocrine therapy (pET) from the WSG‐ADAPT trial (NCT01779206) were analyzed for genetic alterations associated with impaired endocrine proliferative response (EPR) to 3‐week pET with tamoxifen or aromatase inhibitors. EPR was categorized as optimal (post‐pET Ki67 <10%) versus slightly, moderately, and severely impaired (post‐pET Ki67 10%–19%, 20%–34%, and ≥35%, respectively). Recently described gene mutations frequently found in previously treated advanced breast cancer were analyzed (ARID1A, BRAF, ERBB2, ESR1, GATA3, HRAS, KRAS, NRAS, PIK3CA, and TP53) by next‐generation sequencing. Amplifications of CCND1, FGFR1, ERBB2, and PAK1 were determined by digital PCR or fluorescence in situ hybridization. Results ERBB2 amplification (p = 0.0015) and mutations of TP53 (p < 0.0001) were significantly associated with impaired EPR. Impaired EPR in TP53‐mutated breast cancer cases was independent from the Oncotype DX Recurrence Score group and was seen both with tamoxifen‐ and aromatase inhibitor‐based pET (p = 0.0005 each). Conclusion We conclude that impaired EPR to pET is suitable to identify cases with primary endocrine resistance in early luminal breast cancer and that TP53‐mutated luminal cancers might not be sufficiently treated by endocrine therapy alone.

Mutual exclusivity of ESR1 and TP53 mutations in endocrine resistant metastatic breast cancer

“…It is possible that a subpopulation of cells may have potentiated ER signaling following the p53 activation by first-line chemotherapy, which makes them more sensitive towards a subsequent endocrine therapy. This is in line with the recent clinical observation that TP53 mutations are largely associated with endocrine resistance in ER+ breast cancer 69 , 70 , suggesting that a functional p53 is a favorable predictive factor for endocrine therapy. In addition, previous clinical trials showed that chemo-endocrine combination as first-line therapy improved outcomes, as exemplified by aromatase inhibitors plus capecitabine for postmenopausal women 71 and tamoxifen plus CAF (cyclophosphamide, doxorubicin, and fluorouracil) for premenopausal women 72 .…”

Clinical validity and clinical utility of Ki67 in early breast cancer

“…33 Thus, omission of chemotherapy in early BC of premenopausal patients with limited nodal burden and intermediate RS can be based on an easy accessible prognostic marker, provided by Ki67 response to short-term endocrine therapy. 33 Missing Ki67 response to short-term endocrine preoperative therapy was associated with genetic aberrations, potentially conferring endocrine resistance like TP53 mutation, 34 which has also been found in more than 25% of relapsing luminal BCs under therapy. 35 High proliferative activity in BRCA-mutated BC BCs with a germline background of BRCA1 or BRCA2 mutation share some histopathological features like triple negativity but there is no pathognomonic phenotype.…”

Prädiktive molekulare Diagnostik beim Mammakarzinom

“…Eine Pan-Tumor-Zulassung der U.S. Food and Drug Administration (FDA) als Therapie der letzten Wahl für solide Tumoren mit MSI ermöglicht die Selektion weiterer potenziell profitierender Subtypen [ 29 ]. Inaktivierende TP53 -Mutationen sind beim metastasierenden Mammakarzinom häufig und können beim luminalen Tumor eine endokrine Resistenz bedingen ([ 30 ]; Abb. 3 ).…”

“…Inaktivierende TP53 -Mutationen sind beim metastasierenden Mammakarzinom häufig und können beim luminalen Tumor eine endokrine Resistenz bedingen ([ 30 ]; Abb. 3 ).…”