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TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer
Isabel Grote1, Stephan Bartels1, Leonie Kandt1
1Hannover Medical School, Institute of Pathology, Hannover, Germany.
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.
Insights
Genomic alterations like TP53 mutations indicate primary endocrine resistance in early breast cancer. These findings suggest TP53-mutated luminal cancers may require treatment beyond endocrine therapy alone.
Area of Science:
- Oncology
- Genomics
- Breast Cancer Research
Background:
- Genomic landscape of endocrine-resistant breast cancer is well-studied in recurrent cases.
- Little is known about genomic alterations causing primary non-responsiveness to endocrine therapy in early luminal breast cancer.
Purpose of the Study:
- Investigate genetic alterations linked to impaired endocrine proliferative response (EPR) in early luminal breast cancer.
- Identify biomarkers for primary endocrine resistance.
Main Methods:
- Analyzed 622 estrogen receptor-positive breast cancer cases from the WSG-ADAPT trial treated with preoperative endocrine therapy (pET).
- Assessed genetic alterations (mutations and amplifications) using next-generation sequencing and digital PCR/FISH.
- Categorized EPR based on post-pET Ki67 levels.
Main Results:
- ERBB2 amplification and TP53 mutations were significantly associated with impaired EPR.
- TP53 mutations predicted impaired EPR independently of the Oncotype DX Recurrence Score.
- Impaired EPR due to TP53 mutations was observed with both tamoxifen and aromatase inhibitor pET.
Conclusions:
- Impaired EPR to pET effectively identifies primary endocrine resistance in early luminal breast cancer.
- TP53-mutated luminal breast cancers may not respond adequately to endocrine therapy alone.
- Further investigation into treatment strategies for TP53-mutated early breast cancer is warranted.
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