[Nguyen]

Somehow I get the impression that a fair number of bc patients don't get genetic testing and analysis. Perhaps this posting will help and/or motivate you to ask for that.

From SABCS 2023

PO5-24-06

Genomic findings in metastatic breast cancer

Presenting Author(s) and Co-Author(s):
K. Cole. University of Chicago, Chicago, Illinois, United States
M. Tjota. University of Chicago, United States
J. Segal. University of Chicago, United States
P. Wang. University of Chicago, United States
S. Crespo-Ramos. University of Chicago, United States

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<
0.05). Recurrent CCND1, FGFR1 and MYC copy number amplifications were seen almost
exclusively in hormone receptor positive/HER2- tumors (p >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.