• Extensive multi-platform analysis of multiple breast cancer metastases paves the way for developing novel personalized therapies
  • This present study provides new insights into metastatic cell spread, how drug resistance mechanisms differ, and how the immune system recognizes breast cancer metastases.
  • Integrating genomics-driven data and immune landscapes promises more potent immuno-based therapies against refractory breast cancer.

 

Better understanding the molecular biology and mechanisms of advanced metastatic breast cancers can be achieved by unmasking their genomic evolution and processes triggered by the immune system. Published as an Open Access Article in Cell Reports*, findings first authored by Leticia de Mattos-Arruda, Junior Principal Investigator of VHIO’s Applied Genetics of Metastatic Cancer Group, celebrate important progress in this direction and promise new therapeutic avenues for the treatment of these patients.

Carried out in collaboration with Carlos Caldas, Professor of Cancer Medicine, Cancer Research UK Cambridge Institute, Director of the Cambridge Breast Cancer Research Unit, and corresponding and senior author of this present study, the researchers performed extensive multi-platform profiling of each of the regional metastases in autopsies from 10 patients with therapy-resistant breast cancer to establish the genomic and transcriptomic landscapes of individual tumors and the response evoked by the immune system against metastasis.

This research received consent from the families of the ten patients who had died of metastatic breast cancer and underwent extensive autopsies. A total of 241 metastases and primary tumors were identified, and fragments of tumor DNA were analyzed by liquid biopsy.

By characterizing the genomic landscapes of multiple metastases from each patient using multi sequencing platforms, the team have described the heterogeneity between the different metastases and primary tumors. 

“Our results indicate that, in most patients, metastases occur in a small number of propagation events, which emanate from a common genomic ancestor. Their mutations are therefore grouped by clades. In some cases, this might suggest specific tumor resistance mechanisms per subgroup, which could have important implications in better combating resistance to therapy,” explained Leticia de Mattos-Arruda.

The authors also sequenced the immunological receptors of these metastases. They have described how the immune system recognizes neoantigens as foreign bodies as well as demonstrate that they are shared by various metastases in the same patient. The researchers have shown that these tumors lose the ability to present neoantigens, enabling them to ultimately dodge the immune system and become resistant to therapy. She continued, “We have shown that the immune responses of T-cells seem to evolve together with metastatic cancer genomes. This is particularly relevant in the development of more effective immunotherapeutics.”  

“Given the huge amount of data and analyses involved, this work represents a go-to encyclopedia for information on metastatic breast cancer and marks an important milestone in better defining advanced refractory breast cancer, which is a particularly heterogeneous and complex disease,” added Carlos Caldas, senior co-author of this present paper along with Joan Seoane, Co-Program Director of Preclinical and Translational Research at VHIO, ICREA Professor, and Principal Investigator of our Gene Expression & Cancer Group.

In the individual metastases of each patient the researchers also sought to computationally predict the repertoire of abnormal neoantigens or proteins specific to the tumor cells, which are, in turn, recognized by the immune system.

An additional innovative aspect of this study is that the T-lymphocyte receptor was sequenced in each metastasis. “The genomic patterns of metastases and T-cell receptors are very similar. This correlation is no coincidence. These findings may have important implications for personalized vaccination based on neoantigens and on T-cells, which are already under clinical development, observed Leticia.

The authors also established that the immune micro-environments of tumors are not uniform, which has profound implications for therapy with immune checkpoint inhibitors, since, for example, the expression of PD1/PDL1 was different in all the metastases.

Several previous studies have improved our understanding of the molecular ‘machinery’ of primary breast tumors. Tremendous progress within this field has greatly advanced the treatment and care matched to the specificities of these patients.

“However, few have addressed the disease in a metastatic state; nor have genomics been integrated with the tumor micro-environment. With this research we hope that advances can be made in understanding the complexity of these metastases and that ways of developing more effective immunotherapeutics can be identified and rapidly pursued,” concluded Carlos Caldas.

This multi-center research was also conducted in collaboration with other colleagues including Javier Cortés, Associate Translational Investigator at VHIO and Head of the Breast Cancer and Gynecological Tumor Programs at the Ramon y Cajal University Hospital in Madrid, Santiago Ramón y Cajal’s pathology team at the Vall d’Hebron University Hospital (HUVH), and investigators at the Translational Genomics Research Institute (TGEN), Broad Institute, and Dana-Faber Cancer Institute in the USA, the Weizmann Institute in Israel, and the University of Cambridge, UK.

The authors are very grateful to the 10 patients and their families who donated the autopsy and tumor samples with linked clinical data, and VHIO’s Breast Cancer Group and Unit at the Vall d´Hebron University Hospital (HUVH), directed by Cristina Saura.

This study was supported by Cancer Research UK (CRUK). Leticia de Mattos-Arruda’s work was funded by grants received from the CELLEX Foundation and the Spanish Association against Cancer (AECC).

* The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer. Leticia De Mattos-Arruda, Stephen-John Sammut, Edith M. Ross, Rachael Bashford-Rogers, Erez Greenstein, Havell Markus, Sandro Morganella, Yvonne Teng, Yosef Maruvka, Bernard Pereira, Oscar M. Rueda, Suet-Feung Chin, Tania Contente-Cuomo, Regina Mayor, Alexandra Arias, H. Raza Ali, Wei Cope, Daniel Tiezzi, Aliakbar Dariush, Tauanne Dias Amarante, Dan Reshef, Nikaoly Ciriaco, Elena Martinez-Saez, Vicente Peg, Santiago Ramon y Cajal, Javier Cortes, George Vassiliou, Gad Getz, Serena Nik-Zainal, Muhammed Murtaza, Nir Friedman, Florian Markowetz, Joan Seoane, Carlos Caldas. Cell Reports. 27, 2690–2708, May 28, 2019.

https://doi.org/10.1016/j.celrep.2019.04.098

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