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The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer

ABSTRACT: Less than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSC) survive more than five years post-diagnosis but those who have an exceptionally long survival could provide insights into tumor biology and therapeutic approaches. We analyzed 60 patients with advanced-stage, HGSC who survived more than 10 years after diagnosis using whole-genome sequencing, transcriptome, and methylome profiling of their primary tumor samples, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair, and more frequent somatic variants resulting in an increased predicted neoantigen load. Patients clustered into survival groups based on genomic and immune cell signatures, including three subsets of patients with BRCA1 alterations with distinctly different outcomes. Specific combinations of germline and somatic gene alterations, tumor cell phenotypes, and differential immune responses appear to contribute to long-term survival in HGSC.

PROVIDER: EGAS00001005984 | EGA |

REPOSITORIES: EGA

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Project description:Trastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. Some of these patients may become long-term survivors. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression to trastuzumab. 103 patients were registered in the Long-HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Sixty-five per cent of tumours were poorly differentiated ductal carcinomas and hormonal receptors were present in 47%. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median progression-free survival was 10.6 years after the diagnosis of metastatic disease. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival . Gene ontology analysis demonstrated that genes involved in HIF activation, EGF receptor signalling pathway, PI3 kinase pathway, apoptosis signalling pathway and p53 pathway significantly correlated with response. The PI3K pathway was the most strongly associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most. These findings support that trastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression to trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy. 53 FFPE samples, which passed the RNA quality control criteria, were analyzed (45 primary tumours and 8 metastases). Among these 53 samples, 35 samples corresponded to long-term responders and 18 to the control group.

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The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer

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