It is thanks to today’s array of more powerful and targeted therapies that the last two decades have marked important milestones in more effectively treating patients with HER2-positive metastatic breast cancer (HER2+ BC). For patients whose breast cancer has spread to the brain however, as is the case for approximately half of these individuals, there is a critical, unmet clinical need to better understand how this metastatic spread evolves, identify molecular targets and potentiate therapies against brain metastasis – particularly in HER2+ BC.
Findings recently reported open access, ahead of print in the journal Oncotarget*, led by Leticia de Mattos-Arruda, Junior Principal Investigator of VHIO’s Applied Genetics of Metastatic Cancer Group, and Jorge Reis-Filho, Memorial Sloan Kettering Cancer Center – MSKCC (New York), represent a promising next step in this direction.
This multicenter study, carried out in collaboration with investigators from MSKCC, VHIO’s Gene Expression & Cancer and Breast Cancer Groups (headed by Joan Seoane and Cristina Saura), Javier Cortés (Associate Translational Investigator at VHIO and Head of Breast Cancer and Gynecological Tumors, Ramon y Cajal University Hospital, Madrid), the Pathology Service of the Vall d´Hebron University Hospital (Santiago Ramon y Cajal’s team), and colleagues at Dexeus University Hospital, has shown that brain metastases derived from HER2+ BC present different genetic alterations from their respective primary tumors. These identified mutations could therefore serve as therapeutic targets in order to ultimately improve outcomes for these patients.
“We explored the genetic heterogeneity of brain metastases and compared it with that of the primary tumors upon diagnosis. Seizing on the identified genetic alterations and subsequently seeking out new therapeutic avenues for these patients is critical. While targeted therapies have certainly led to hugely increased survival rates for breast cancer patients with HER2+ metastatic disease, survival of those individuals with brain metastases have unfortunately failed to significantly decline”, explains Leticia de Mattos-Arruda.
In order to compare which genes were modified in each metastatic breast cancer and brain metastasis, the researchers assessed samples from the brain tumors collected upon surgical excision or post-mortem examination.
Using massive parallel sequencing targeting a panel of 254 genes frequently mutated in breast cancer, the authors found that four out of the six patients with brain metastasis (67%) harbored at least one genetic alteration private to, or enriched in brain metastases that could potentially be clinically targetable. By comparing the respective primary tumor and brain lesion pairings, they identified that the metastases presented genetic mutations that were not found in the primary tumors including alterations in FGFR2, PI3KCA and ATR, and deletions in CDKN2A and amplifications in KRAS.
Additionally, they observed that throughout the course of treatment with chemotherapy and HER2 inhibitors, additional mutations arose and that some of these identified mutations, such as those located in FGFR2 and PI3KCA, or deletions in CDKN2A – for which approved inhibitors already exist – could serve as therapeutic targets.
Their results suggest that different subtypes of HER2-postitive breast cancer patients may be defined based on their repertoire of genetic alterations in the brain metastasis and potential targeted agents directed against these alterations would need to be subsequently tested in extended groups of patients within the context of clinical trials.
“Importantly, up until now, upon disease progression, physicians typically rely on data from primary breast tumors in these patients in order to help guide treatment decisions. Applying liquid biopsies, particularly cell-free DNA from cerebrospinal fluid, will be important to capture the private or enriched actionable genetic alterations present in brain metastases”, concludes Leticia.
The authors acknowledge the CELLEX Foundation and the Rafael del Pino Foundation for supporting the development of this research.
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