Abstract PO5-24-06: Genomic findings in metastatic breast cancer
Authors: Cole Kimberly , Tjota Melissa , Segal Jeremy , Wang Peng , Crespo-Ramos Susanne 
Published: May 2024

Introduction: Although metastatic breast cancer is the second leading cause of cancer death in women, the genomic findings in metastatic breast cancer are not as well characterized as those of primary breast cancers. Metastatic tumors are genetically heterogenous, enriched for resistance mutations, and often lack targetable alterations. Improved understanding of the molecular mechanisms that drive metastatic disease of all receptor subtypes is required to identify possible molecular targets and to develop new targeted therapies in an effort to reduce the mortality.

Methods: A cohort of 50 metastatic breast cancer cases (n=33 ER+/PR+, n=3 ER+/HER2+, n=3 ER-/HER2+ n=11 TNBC) sequenced at our medical center between 2018-2023 was evaluated, and the molecular findings of the major subtypes were analyzed. Genomic data included mutations, copy number alterations, tumor mutation burden and microsatellite instability.

Results: The most frequent somatic alteration were PIK3CA mutations, involving 17/33 of ER+/PR+/HER- tumors, 5/11 TNBC tumors and 5/6 HER+ cases. TP53 mutations (frameshift and missense) were more frequently identified in TNBC and HER2+ cases (p&lt; 0.05). Recurrent CCND1, FGFR1 and MYC copy number amplifications were seen almost exclusively in hormone receptor positive/HER2- tumors (p &gt;0.05). ESR1 mutations involved 15% of the ER positive cancers and were frequently associated with co-occurring CCND1 and FGFR1 copy number gains. Significant genomic losses that drive tumorigenesis were also detected. Both CDKN2a and PTEN deletions were found in ER/PR positive disease, as well as triple negative tumors. Genomic deletions associated with worse outcomes such as TP53 and DICER1 were also detected. ERBB2 amplification was 100% concordant with our immunohistochemical and FISH results for the 6 HER2 positive cases. All 50 cases demonstrated a low tumor mutation burden and were microsatellite stable.

Conclusion: We detected driver alterations that involve multiple pathways including estrogen receptor signaling, PI3K/AKT/MTOR, the cell cycle, and receptor tyrosine kinases. The genomic alterations are enriched for resistance mechanisms, like ESR1 mutations and FGFR1 gains that mediate resistance to endocrine treatment, as well as PIK3CA, also implicated in both endocrine and HER2-targeting therapy resistance. Of particular interest, were the amplifications detected in the ER+/PR+ tumors, such as CCND1 on chromosome 11q, FGFR1 on 8p and MYC on 8q, which were detected in almost half (45%) of our hormone receptor positive cohort. Some of the identified driver amplifications also define a subset of the Integrated Molecular Subtypes (Curtis et al., Nature; 486(7403): 346–352), i.e., Clusters 2, 6 and 9 that are typically hormone receptor positive but associated with either a very poor prognosis (Cluster 2) or an intermediate prognosis (Clusters 6 and 9), unlike the copy neutral ER positive tumors or those with the classic 1p and 16q alterations. Therefore, copy number profiling of advanced-stage breast cancers may be a useful tool for determining prognosis, identifying possible targetable driver pathways and selecting appropriate patients for molecularly guided clinical trials.

Citation Format: Kimberly Cole, Melissa Tjota, Jeremy Segal, Peng Wang, Susanne Crespo-Ramos. Genomic findings in metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-24-06.